62 results on '"Shripad S. Bhagwat"'
Search Results
2. 4-Amino-5-aryl-6-arylethynylpyrimidines: Structure–activity relationships of non-nucleoside adenosine kinase inhibitors
- Author
-
Steven W. Muchmore, Elizabeth A. Kowaluk, Kennan C. Marsh, Steve McGaraughty, Haixia Yu, Arthur Gomtsyan, Andrew O. Stewart, Shripad S. Bhagwat, Michael F. Jarvis, Karen M. Alexander, Kathy L. Kohlhaas, Clarissa L. Jakob, Chih-Hung Lee, Robin R. Frey, Mark A. Matulenko, Ernest S. Paight, Joseph P. Mikusa, Meiqun Jiang, and Stanley Didomenico
- Subjects
Protein Conformation ,Stereochemistry ,Morpholines ,Clinical Biochemistry ,Pharmaceutical Science ,Adenosine kinase ,Crystallography, X-Ray ,Biochemistry ,Rats, Sprague-Dawley ,Inhibitory Concentration 50 ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,medicine ,Animals ,Structure–activity relationship ,Binding site ,Adenosine Kinase ,Molecular Biology ,Binding Sites ,biology ,Chemistry ,Aryl ,Organic Chemistry ,Active site ,Ligand (biochemistry) ,Adenosine ,Rats ,Pyrimidines ,biology.protein ,Molecular Medicine ,Nucleoside ,Protein Binding ,medicine.drug - Abstract
A series of non-nucleoside adenosine kinase (AK) inhibitors is reported. These inhibitors originated from the modification of 5-(3-bromophenyl)-7-(6-morpholin-4-ylpyridin-3-yl)pyrido[2,3-d]pyrimidin-4-ylamine (ABT-702). The identification of a linker that would approximate the spatial arrangement found between the pyrimidine ring and the aryl group at C(7) in ABT-702 was a key element in this modification. A search of potential linkers led to the discovery of an acetylene moiety as a suitable scaffold. It was hypothesized that the aryl acetylenes, ABT-702, and adenosine bound to the active site of AK (closed form) in a similar manner with respect to the orientation of the heterocyclic base. Although potent acetylene analogs were discovered based on this assumption, an X-ray crystal structure of 5-(4-dimethylaminophenyl)-6-(6-morpholin-4-ylpyridin-3-ylethynyl)pyrimidin-4-ylamine (16a) revealed a binding orientation contrary to adenosine. In addition, this compound bound tightly to a unique open conformation of AK. The structure-activity relationships and unique ligand orientation and protein conformation are discussed.
- Published
- 2007
3. 5-(3-Bromophenyl)-7-(6-morpholin-4-ylpyridin-3-yl)pyrido[2,3-d]pyrimidin-4-ylamine: structure–activity relationships of 7-substituted heteroaryl analogs as non-nucleoside adenosine kinase inhibitors
- Author
-
Meiqun Jiang, Stanley Didomenico, Ronald D. Snyder, Karen M. Alexander, Shripad S. Bhagwat, Guo Zhu Zheng, Carol T. Wismer, Haixia Yu, Andrew O. Stewart, Marilyn S. Diehl, Gregory A. Gfesser, Kennan C. Marsh, Erol K. Bayburt, Robin R. Frey, Mark A. Matulenko, Marlon D. Cowart, Jeffery A. McKie, Arthur Gomtsyan, Kathy L. Kohlhaas, Michael F. Jarvis, Elizabeth A. Kowaluk, Joseph P. Mikusa, Steve McGaraughty, and Chih-Hung Lee
- Subjects
Male ,Magnetic Resonance Spectroscopy ,Stereochemistry ,Morpholines ,Clinical Biochemistry ,Pharmaceutical Science ,Adenosine kinase ,Ring (chemistry) ,Biochemistry ,Mass Spectrometry ,Cell Line ,Ames test ,Rats, Sprague-Dawley ,Structure-Activity Relationship ,In vivo ,Drug Discovery ,Animals ,Structure–activity relationship ,Enzyme Inhibitors ,Adenosine Kinase ,Molecular Biology ,chemistry.chemical_classification ,biology ,Organic Chemistry ,Rats ,Pyrimidines ,Enzyme ,chemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,Nucleoside - Abstract
4-Amino-5,7-disubstituted pyridopyrimidines are potent, non-nucleoside inhibitors of adenosine kinase (AK). We recently identified a potent, orally efficacious analog, 4 containing a 7-pyridylmorpholine substituted ring system as the key structural element of this template. In this report, we disclose the pharmacologic effects of five- and six-membered heterocyclic ring replacements for the pyridine ring in 4. These replacements were found to have interesting effects on in vivo efficacy and genotoxicity as well as in vitro potency. We discovered that the nitrogen in the heterocyclic ring at C(7) is important for the modulation of mutagenic side effects (Ames assay).
- Published
- 2005
4. Synthesis and biological evaluation of 6,7-disubstituted 4-aminopyrido[2,3-d]pyrimidines as adenosine kinase inhibitors
- Author
-
Kathy L. Kohlhaas, Richard J. Perner, Chih-Hung Lee, Erol K. Bayburt, Karen M. Alexander, Michael F. Jarvis, Elizabeth L. Kowaluk, Shripad S. Bhagwat, Gu Yu-Gui, Meiqun Jiang, and Stanley Didomenico
- Subjects
Stereochemistry ,Clinical Biochemistry ,Drug Evaluation, Preclinical ,Pharmaceutical Science ,Adenosine kinase ,Biochemistry ,Chemical synthesis ,chemistry.chemical_compound ,Drug Discovery ,Potency ,Enzyme Inhibitors ,Adenosine Kinase ,Molecular Biology ,chemistry.chemical_classification ,biology ,Bicyclic molecule ,Aryl ,Organic Chemistry ,In vitro ,Pyrimidines ,Enzyme ,chemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine - Abstract
The synthesis and structure-activity relationship of a series of 6,7-disubstituted 4-aminopyrido[2,3-d]pyrimidines as novel non-nucleoside adenosine kinase inhibitors is described. A variety of substituents, primarily aryl, at the C6 and C7 positions of the pyridopyrimidine core were found to yield analogues that are potent inhibitors of adenosine kinase. In contrast to the 5,7-disubstituted and 5,6,7-trisubstituted pyridopyrimidine series, these analogues exhibited only modest potency to inhibit AK in intact cells.
- Published
- 2005
5. Differential Response of Estrogen Receptors α and β to SP500263, a Novel Potent Selective Estrogen Receptor Modulator
- Author
-
Adam Kois, Bernd Stein, Graciella Shevlin, May S Kung Sutherland, Steve Pierce, Shripad S. Bhagwat, Stephanie Lipps, Helen Brady, Leah M. Gayo-Fung, Matt Hickman, Mary Doubleday, David W. Anderson, Normand Richard, and Khammungkhune Sak
- Subjects
medicine.drug_class ,Gene Expression ,Estrogen receptor ,Enzyme-Linked Immunosorbent Assay ,Pharmacology ,Biology ,Response Elements ,Estrogen-related receptor alpha ,Piperidines ,Coumarins ,Tumor Cells, Cultured ,medicine ,Estrogen Receptor beta ,Humans ,Selective receptor modulator ,Cells, Cultured ,Estrogen receptor beta ,Interleukin-6 ,Estrogen Antagonists ,Estrogen Receptor alpha ,Granulocyte-Macrophage Colony-Stimulating Factor ,Receptors, Estrogen ,Selective estrogen receptor modulator ,Estrogen ,Molecular Medicine ,Estrogen-related receptor gamma ,Estrogen receptor alpha ,hormones, hormone substitutes, and hormone antagonists - Abstract
We determined the differential response of a novel SERM, SP500263, on estrogen receptor (ER) alpha and the more recently cloned ER-beta. Because of the high homology of amino acid residues in the ligand-binding domain of ER-alpha and ER-beta, we were not surprised to find that SP500263 binds to both ERs equally well. In contrast, SP500263 acts as a strong estrogen agonist in a strictly ER-alpha-specific manner in U2OS osteosarcoma cell lines blocking the production of interleukin (IL) 6 and granulocyte macrophage colony-stimulating factor. SP500263 also blocked IL-6 production in primary bone cells. The mechanism of this inhibition is different from the classic estrogen stimulation involving an estrogen response element (ERE). SP500263 does not activate gene expression through an ERE. In contrast to the results observed in U2OS cells, SP500263 acts as a strong estrogen antagonist in an MCF-7 breast cancer proliferation assay. Therefore, SP500263 is a member of a series of next-generation SERMs with functional selectivity toward ER-alpha and a mixed agonist/antagonist profile in a bone cell assay versus a breast cancer assay. The panel of assays described herein allow for the development of receptor-specific ligands that may be further developed into novel pharmaceuticals with an improved profile for the treatments of osteoporosis and breast cancer.
- Published
- 2002
6. Abstract 849: Molecular characterization of primary tumor & the paired liver metastatic biopsies of colorectal cancer reveals a critical role of immunosuppression, EMT & angiogenesis in cancer metastasis
- Author
-
Hye Kyung Hong, John N. Calley, Christoph Reinhard, Jiangang Liu, Do-Hyun Nam, Robert A. Wild, Yong Beom Cho, Jason C. Ting, Shripad S. Bhagwat, Philip J. Ebert, Sheng-Bin Peng, Amit Aggarwal, Steven M. Bray, Woo Yong Lee, Swee Seong Wong, Emma T. Bowden, Song Wu, and Catherine F. Whittington
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Angiogenesis ,Colorectal cancer ,business.industry ,medicine.medical_treatment ,Cancer metastasis ,Immunosuppression ,medicine.disease ,Primary tumor ,Internal medicine ,medicine ,business - Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. In United States alone, it was estimated that nearly 137,000 people were diagnosed, and more than 50,000 were dead from the disease each year. CRC primary tumors often metastasize to liver which accounts for most of CRC death. The molecular mechanism of tumor metastasis is complicate and remains poorly understood. In this study, we have collected 79 human CRC samples, and 60 of them are paired primary tumor and liver metastatic surgically resected samples. Molecular characterization of these samples was conducted by exome and RNA sequencing, as well as SNP6.0 analysis. Genetic analysis revealed no significant difference in genetic alterations including common oncogenic mutations, whole genome mutations and copy number variations between primary and their matched liver metastatic tumors. To further characterize the molecular mechanism of metastatic progression, we have assembled gene correlation networks by utilizing a genome-wide interrogation of co-regulated networks based on RNA sequencing data of these CRC samples. Computational analysis of these correlation networks has identified gene signatures of immune-suppression, epithelial-mesenchymal transition (EMT) and angiogenesis as the key events and potentially synergistic drivers associated with CRC metastasis. Further independent cohort validation using published datasets verified that these specific gene networks of tumor microenvironment were progressively up-regulated throughout the carcinogenesis, and represented distinct biological processes. These gene networks were capable of discriminating the previously categorized CRC molecular subclasses. In addition, we also showed an association of type I interferon network with good clinical outcome of CRC, and gene networks of EMT, angiogenesis, immune-suppression and T cell exhaustion are closely associated with the poor patient outcome. We further demonstrated that the networks of EMT and angiogenesis were related to innate anti-PD-1 resistance, and the networks of immunosuppression and T cell exhaustion were associated with resistance to radiation and checkpoint blockade. Overall, we conclude that a genome-wide interrogation of co-regulated networks utilized in this study represents a valuable strategy to identify molecular mechanisms of cancer metastasis, and gene networks of immune-suppression, EMT and angiogenesis are among the key events associated with CRC metastasis. Citation Format: Jiangang Liu, Yong Beom Cho, Hye kyung Hong, Song Wu, Philip J. Ebert, Steven M. Bray, Swee Seong Wong, Jason C. Ting, John N. Calley, Catherine F. Whittington, Shripad Bhagwat, Emma Bowden, Amit Aggarwal, Christoph Reinhard, Robert Wild, Do-Hyun Nam, Woo Yong Lee, Sheng-Bin Peng. Molecular characterization of primary tumor & the paired liver metastatic biopsies of colorectal cancer reveals a critical role of immunosuppression, EMT & angiogenesis in cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 849. doi:10.1158/1538-7445.AM2017-849
- Published
- 2017
7. Synthesis and biological evaluation of clitocine analogues as adenosine kinase inhibitors
- Author
-
Karen M. Alexander, Michael F. Jarvis, Chih-Hung Lee, Haixia Yu, Shripad S. Bhagwat, Kathy L. Kohlhaas, Jerome F. Daanen, Elizabeth L. Kowaluk, and Meiqun Jiang
- Subjects
Clinical Biochemistry ,Drug Evaluation, Preclinical ,Pharmaceutical Science ,Adenosine kinase ,Biochemistry ,Clitocybe ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,medicine ,Animals ,Potency ,Enzyme Inhibitors ,Adenosine Kinase ,Molecular Biology ,chemistry.chemical_classification ,biology ,Organic Chemistry ,Pyrimidine Nucleosides ,biology.organism_classification ,Adenosine ,In vitro ,Rats ,Enzyme ,chemistry ,Enzyme inhibitor ,Clitocine ,Drug Design ,biology.protein ,Molecular Medicine ,medicine.drug - Abstract
Adenosine kinase (AK) is the primary enzyme responsible for adenosine metabolism. Inhibition of AK effectively increases extracellular adenosine concentrations and represents an alternative approach to enhance the beneficial actions of adenosine as compared to direct-acting receptor agonists. Clitocine (3), isolated from the mushroom Clitocybe inversa, has been found to be a weak inhibitor of AK. We have prepared a number of analogues of clitocine in order to improve its potency and demonstrated that 5'-deoxy-5'-amino-clitocine (7) improved AK inhibitory potency by 50-fold.
- Published
- 2001
8. N-aryl cinnamides: A novel class of rigid and highly potent leukotriene B4 receptor antagonists
- Author
-
Michael H. Chin, Huanghai Zhou, Main Alan J, Susan Uziel-Fusi, Lester I. Barsky, Shripad S. Bhagwat, Kenneth E. Lipson, R. H. Jackson, Robert A. Doti, Alan R. Engle, Paul D. Greenspan, and Lisa M. Frey
- Subjects
Leukotriene B4 ,medicine.drug_class ,Ligand binding assay ,Organic Chemistry ,Clinical Biochemistry ,Leukotriene B4 receptor ,Pharmaceutical Science ,Carboxamide ,Biochemistry ,In vitro ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,medicine ,Molecular Medicine ,Antagonism ,Receptor ,Molecular Biology ,Neutrophil aggregation - Abstract
A series of N-aryl cinnamides has been prepared and assayed for antagonism of the leukotriene B4 receptor. Several compounds in this series were found to be highly potent antagonists of the human neutrophil receptor, based on a whole cell binding assay, as well as a neutrophil aggregation assay. This series is unique among LTB4 antagonists, due to its high degree of rigidity.
- Published
- 1997
9. Synthesis of enantiomerically pure pyrrolidinones as endothelin receptor antagonists
- Author
-
Shripad S. Bhagwat, Kenneth Chan, and Candido Gude
- Subjects
Stereochemistry ,Organic Chemistry ,Imine ,Diastereomer ,Biochemistry ,Chloride ,Cycloaddition ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,medicine ,Organic chemistry ,Pyrrolidinones ,Endothelin receptor ,medicine.drug - Abstract
Enantiomerically pure pyrrolidinones were synthesized as endothelin receptor antagonists. A [2+2] cycloaddition of an imine and an enantiomerically pure acid chloride gave two diastereomeric β-lactams which were separated and rearranged to give the enantiomerically pure pyrrolidinones which could be reduced to give the corresponding pyrrolidines.
- Published
- 1996
10. Patent Update Cardiovascular & Renal: Recent progress in modulators of purinergic activity
- Author
-
Shripad S. Bhagwat and Michael Williams
- Subjects
Pharmacology ,Purine ,Purinergic receptor ,Antagonist ,General Medicine ,P2 receptor ,Biology ,Adenosine A1 receptor ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,Selective receptor modulator ,Receptor ,Nucleoside - Abstract
As knowledge of the molecular biology of purinergic receptors continues to evolve, the identification of novel compounds that mimic or block the actions of the purine nucleoside and its nucleotide, ATP, at P1 and P2 receptor subtypes, respectively, has continued to be an area of active interest in the pharmaceutical industry. Adenosine A1 receptor selective agonists with reduced cardiovascular liabilities have been recently described, as have novel A3 receptor selective agonists; both classes of agents showing potential as anti-ischaemic agents in animal models. A number of potent and receptor subtype selective agonists for P2 receptors have also been developed that are being used to characterise the functional role of this receptor class in various mammalian tissues. On the antagonist front, selective A1 receptor antagonists are being targeted as cognition enhancers while selective A2a receptor antagonists have been developed with potential use in Parkinson's disease therapy. Despite the clinical failure...
- Published
- 1995
11. α-Mercaptoacyl dipeptides that inhibit angiotensin converting enzyme and neutral endopeptidase 24.11
- Author
-
Ying Qiao, Carol Berry, Kenneth Chan, Shripad S. Bhagwat, Raj D. Ghai, Cynthia A. Fink, Candido Gude, and Yumi Sakane
- Subjects
chemistry.chemical_classification ,Carbon atom ,biology ,Chemistry ,Stereochemistry ,fungi ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Angiotensin-converting enzyme ,Biochemistry ,Amino acid ,Drug Discovery ,Thiol ,biology.protein ,Molecular Medicine ,Neutral Endopeptidase 24.11 ,Proline ,Molecular Biology ,Ace inhibition ,Neprilysin - Abstract
α-Mercaptoacyl dipeptides were prepared and found to inhibit angiotensin converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP). Compounds with a proline as the C-terminal amino acid, and possessing the S-stereochemistry at the thiol bearing carbon were preferred for optimal ACE inhibition while, R-stereochemistry was preferred for optimal NEP inhibition. Compounds containing alternative amino acid residues at the C-terminal position displayed optimal dual ACE/NEP inhibition when the stereochemistry was ‘S’ at this carbon atom.
- Published
- 1995
12. CEP-32496: a novel orally active BRAF(V600E) inhibitor with selective cellular and in vivo antitumor activity
- Author
-
Mangeng Cheng, Kathryn Hunter, Bruce D. Dorsey, Bruce Ruggeri, Dana Gitnick, Martin W. Rowbottom, Pawel Dobrzanski, Michael Williams, Darren E. Insko, Michael F. Gardner, Merryl Cramer, Ruwanthi N. Gunawardane, Susan Jones-Bolin, Mehran Yazdanian, Raffaella Faraoni, Julius L. Apuy, Shripad S. Bhagwat, Mark W. Holladay, Robert C. Armstrong, Hugh Zhao, Joyce James, Ronald R. Nepomuceno, and Mark A. Ator
- Subjects
Sorafenib ,Male ,Proto-Oncogene Proteins B-raf ,Cancer Research ,Colorectal cancer ,Administration, Oral ,Mice, Nude ,Antineoplastic Agents ,Pharmacology ,Rats, Sprague-Dawley ,Mice ,Dogs ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Vemurafenib ,neoplasms ,Cell Proliferation ,business.industry ,Kinase ,Melanoma ,Phenylurea Compounds ,Cancer ,medicine.disease ,digestive system diseases ,Rats ,Macaca fascicularis ,Oncology ,Quinazolines ,Drug Screening Assays, Antitumor ,business ,V600E ,medicine.drug - Abstract
Mutations in the BRAF gene have been identified in approximately 7% of cancers, including 60% to 70% of melanomas, 29% to 83% of papillary thyroid carcinomas, 4% to 16% colorectal cancers, and a lesser extent in serous ovarian and non–small cell lung cancers. The V600E mutation is found in the vast majority of cases and is an activating mutation, conferring transforming and immortalization potential to cells. CEP-32496 is a potent BRAF inhibitor in an in vitro binding assay for mutated BRAFV600E (Kd BRAFV600E = 14 nmol/L) and in a mitogen-activated protein (MAP)/extracellular signal–regulated (ER) kinase (MEK) phosphorylation (pMEK) inhibition assay in human melanoma (A375) and colorectal cancer (Colo-205) cell lines (IC50 = 78 and 60 nmol/L). In vitro, CEP-32496 has multikinase binding activity at other cancer targets of interest; however, it exhibits selective cellular cytotoxicity for BRAFV600E versus wild-type cells. CEP-32496 is orally bioavailable in multiple preclinical species (>95% in rats, dogs, and monkeys) and has single oral dose pharmacodynamic inhibition (10–55 mg/kg) of both pMEK and pERK in BRAFV600E colon carcinoma xenografts in nude mice. Sustained tumor stasis and regressions are observed with oral administration (30–100 mg/kg twice daily) against BRAFV600E melanoma and colon carcinoma xenografts, with no adverse effects. Little or no epithelial hyperplasia was observed in rodents and primates with prolonged oral administration and sustained exposure. CEP-32496 benchmarks favorably with respect to other kinase inhibitors, including RAF-265 (phase I), sorafenib, (approved), and vemurafenib (PLX4032/RG7204, approved). CEP-32496 represents a novel and pharmacologically active BRAF inhibitor with a favorable side effect profile currently in clinical development. Mol Cancer Ther; 11(4); 930–41. ©2012 AACR.
- Published
- 2012
13. 4-Substituted proline derivatives that inhibit angiotensin converting enzyme and neutral endopeptidase 24.11
- Author
-
Ying Qiao, Shripad S. Bhagwat, Raj D. Ghai, Cynthia A. Fink, Kenneth Chan, Candido Gude, Yumi Sakane, and Carol Berry
- Subjects
biology ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Substituent ,Pharmaceutical Science ,Captopril ,Angiotensin-converting enzyme ,Ring (chemistry) ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,medicine ,biology.protein ,Molecular Medicine ,cardiovascular diseases ,Proline ,Neutral Endopeptidase 24.11 ,Enalapril ,Molecular Biology ,Neprilysin ,hormones, hormone substitutes, and hormone antagonists ,circulatory and respiratory physiology ,medicine.drug - Abstract
Analogs of captopril and enalapril with a thiorphan-like substituent at the 4-position of the proline ring were synthesized and found to be dual inhibitors of angiotensin converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP).
- Published
- 1994
14. N-alkylation of indole ring using Mitsunobu reaction
- Author
-
Candido Gude and Shripad S. Bhagwat
- Subjects
Indole test ,chemistry ,Organic Chemistry ,Drug Discovery ,Polar effect ,Organic chemistry ,chemistry.chemical_element ,Mitsunobu reaction ,Alkylation ,Ring (chemistry) ,Biochemistry ,Nitrogen - Abstract
Indole rings substituted with two electron withdrawing groups were alkylated on the nitrogen under Mitsunobu reaction conditions.
- Published
- 1994
15. Aminopurine based JNK inhibitors for the prevention of ischemia reperfusion injury
- Author
-
Elise Sudbeck, Jason Katz, Adam Kois, Brydon L. Bennett, Steven S. Clareen, Michael A. Shirley, Rachel Fan, Shripad S. Bhagwat, Jonathan Wright, Ronald Albers, Brian E. Cathers, Maria Celeridad, Lisa Nadolny, Yang Tang, Sogole Bahmanyar, Heather Raymon, Sutapa Ghosh, David Giegel, Henderson Ian, Philip P Chamberlain, Mehran F. Moghaddam, Kevin S. Hughes, Brent Benish, Kate Blease, Sema Pai, Veronique Plantevin Krenitsky, Jacek Nowakowski, Robert Hilgraf, Mercedes Delgado, Paul Omholt, Yoshitaka Satoh, Jeff Muir, Kiran Sahasrabudhe, Leticia Ayala, Andrew G. Cole, Oleg Khatsenko, and Li Xu
- Subjects
Models, Molecular ,Clinical Biochemistry ,Ischemia ,Pharmaceutical Science ,2-Aminopurine ,Pharmacology ,Biochemistry ,Enzyme activator ,chemistry.chemical_compound ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Dogs ,Catalytic Domain ,Drug Discovery ,medicine ,Potency ,Structure–activity relationship ,Animals ,Enzyme Inhibitors ,Molecular Biology ,Molecular Structure ,Chemistry ,Kinase ,Organic Chemistry ,JNK Mitogen-Activated Protein Kinases ,Haplorhini ,medicine.disease ,Rats ,Enzyme Activation ,Purines ,Reperfusion Injury ,Molecular Medicine ,Reperfusion injury ,Aminopurine - Abstract
In this Letter we describe the optimization of an aminopurine lead (1) with modest potency and poor overall kinase selectivity which led to the identification of a series of potent, selective JNK inhibitors. Improvement in kinase selectivity was enabled by introduction of an aliphatic side chain at the C-2 position. CC-359 (2) was selected as a potential clinical candidate for diseases manifested by ischemia reperfusion injury.
- Published
- 2011
16. ChemInform Abstract: Thromboxane Receptor Antagonism Combined with Thromboxane Synthase Inhibition. Part 1. (.+-.)-(3-Pyridinylbicycloheptyl)alkanoic Acids
- Author
-
P. Furness, Frank H Clarke, Shripad S. Bhagwat, David Cohen, Candido Gude, and W. Lee
- Subjects
chemistry.chemical_classification ,Thromboxane receptor ,Enzyme ,chemistry ,Biochemistry ,biology ,biology.protein ,General Medicine ,Thromboxane-A synthase ,Antagonism - Published
- 2010
17. ChemInform Abstract: Thromboxane Receptor Antagonism Combined with Thromboxane Synthase Inhibition. Part 8. N-Alkylation of the Indole Ring Using the Mitsunobu Reaction
- Author
-
Candido Gude and Shripad S. Bhagwat
- Subjects
Indole test ,Thromboxane receptor ,biology ,Stereochemistry ,Chemistry ,biology.protein ,Mitsunobu reaction ,General Medicine ,Thromboxane-A synthase ,Alkylation ,Ring (chemistry) ,Antagonism - Published
- 2010
18. ChemInform Abstract: 4-Substituted Proline Derivatives that Inhibit Angiotesin Converting Enzyme and Neutral Endopeptidase 24.11
- Author
-
Yumi Sakane, Candido Gude, Carol Berry, Ying Qiao, Kenneth Chan, Cynthia A. Fink, R. D. Ghai, and Shripad S. Bhagwat
- Subjects
chemistry.chemical_classification ,Enzyme ,Chemistry ,Stereochemistry ,General Medicine ,Proline ,Neutral Endopeptidase 24.11 ,Combinatorial chemistry - Published
- 2010
19. ChemInform Abstract: Synthesis of Enantiomerically Pure Pyrrolidinones as Endothelin Receptor Antagonists
- Author
-
Candido Gude, Kenneth Chan, and Shripad S. Bhagwat
- Subjects
chemistry.chemical_compound ,chemistry ,Imine ,medicine ,Diastereomer ,General Medicine ,Pyrrolidinones ,Endothelin receptor ,Medicinal chemistry ,Chloride ,Pyrrole derivatives ,Cycloaddition ,medicine.drug - Abstract
Enantiomerically pure pyrrolidinones were synthesized as endothelin receptor antagonists. A [2+2] cycloaddition of an imine and an enantiomerically pure acid chloride gave two diastereomeric β-lactams which were separated and rearranged to give the enantiomerically pure pyrrolidinones which could be reduced to give the corresponding pyrrolidines.
- Published
- 2010
20. ChemInform Abstract: N-Aryl Cinnamides: A Novel Class of Rigid and Highly Potent Leukotriene B4 Receptor Antagonists
- Author
-
Kenneth E. Lipson, Huanghai Zhou, Lester I. Barsky, Robert A. Doti, Alan R. Engle, Paul D. Greenspan, Lisa M. Frey, R. H. Jackson, Michael H. Chin, Main Alan J, Shripad S. Bhagwat, and Susan Uziel-Fusi
- Subjects
chemistry.chemical_compound ,Human neutrophil ,Chemistry ,Stereochemistry ,Aryl ,Ligand binding assay ,Leukotriene B4 receptor ,General Medicine ,Antagonism ,Receptor ,Whole cell ,Neutrophil aggregation - Abstract
A series of N-aryl cinnamides has been prepared and assayed for antagonism of the leukotriene B4 receptor. Several compounds in this series were found to be highly potent antagonists of the human neutrophil receptor, based on a whole cell binding assay, as well as a neutrophil aggregation assay. This series is unique among LTB4 antagonists, due to its high degree of rigidity.
- Published
- 2010
21. ChemInform Abstract: Adenosine Kinase Inhibitors
- Author
-
Michael F. Jarvis, Elizabeth A. Kowaluk, and Shripad S. Bhagwat
- Subjects
biology ,Kinase ,Chemistry ,Endogeny ,Inflammation ,General Medicine ,Adenosine kinase ,Pharmacology ,Adenosine ,medicine ,Extracellular ,biology.protein ,medicine.symptom ,Receptor ,Intracellular ,medicine.drug - Abstract
Adenosine (ADO) is an endogenous modulator of intercellular signaling that provides homeostatic reductions in cell excitability during tissue stress and trauma. The inhibitory actions of ADO are mediated by interactions with specific cell-surface G-protein coupled receptors regulating membrane cation flux, polarization, and the release of excitatory neurotransmitters. ADO kinase (AK; EC 2.7.1.20) is the key intracellular enzyme regulating intra- and extracellular ADO concentrations. Inhibition of AK produces marked increases in extracellular ADO levels that are localized to cells and tissues undergoing accelerated ADO release. Thus AK inhibition represents a mechanism to selectively enhance the protective actions of ADO during tissue trauma without producing the nonspecific effects associated with the systemic administration of ADO receptor agonists. During the last 10 years, specific inhibitors of AK based on the endogenous purine nucleoside substrate, ADO, have been developed. Potent AK inhibitors have recently been synthesized that demonstrate high specificity for this enzyme as compared to other ADO metabolic enzymes, transporters, and receptors. In both in vitro and in vivo models, AK inhibitors have been shown to potently increase ADO concentrations in a tissue and event specific fashion and to demonstrate potential clinical utility in animal models of epilepsy, ischemia, pain, and inflammation. AK inhibitors have demonstrated superior efficacy in these models as compared to other mechanisms of modulating ADO availability, and these agents exhibit reduced side-effect liabilities compared to direct acting ADO receptor agonists. The preclinical profile of AK inhibitors indicate that these agents may have therapeutic utility in a variety of central and peripheral diseases associated with cellular trauma and inflammation. Clinical trials are currently underway to evaluate the efficacy of AK inhibitors in seizure disorders and pain.
- Published
- 2010
22. ChemInform Abstract: Synthesis and Biological Evaluation of Clitocine Analogues as Adenosine Kinase Inhibitors
- Author
-
Haixia Yu, Chih-Hung Lee, Karen M. Alexander, Kathy L. Kohlhaas, Michael F. Jarvis, Jerome F. Daanen, Elizabeth L. Kowaluk, Shripad S. Bhagwat, and Meiqun Jiang
- Subjects
chemistry.chemical_classification ,biology ,General Medicine ,Adenosine kinase ,Pharmacology ,biology.organism_classification ,Adenosine ,Clitocybe ,chemistry.chemical_compound ,Enzyme ,chemistry ,Clitocine ,biology.protein ,medicine ,Extracellular ,Potency ,Receptor ,medicine.drug - Abstract
Adenosine kinase (AK) is the primary enzyme responsible for adenosine metabolism. Inhibition of AK effectively increases extracellular adenosine concentrations and represents an alternative approach to enhance the beneficial actions of adenosine as compared to direct-acting receptor agonists. Clitocine (3), isolated from the mushroom Clitocybe inversa, has been found to be a weak inhibitor of AK. We have prepared a number of analogues of clitocine in order to improve its potency and demonstrated that 5'-deoxy-5'-amino-clitocine (7) improved AK inhibitory potency by 50-fold.
- Published
- 2010
23. Thromboxane receptor antagonism combined with thromboxane synthase inhibition. 6. 4-substituted 3-pyridinylalkanoic acids
- Author
-
Ronald Dotson, Suraj S. Shetty, David Cohen, C. Boswell, W. Lee, J. Mathis, Candido Gude, N. Contardo, and Shripad S. Bhagwat
- Subjects
biology ,Chemistry ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,Thromboxane receptor ,Thromboxane A2 ,chemistry.chemical_compound ,Drug Discovery ,biology.protein ,Molecular Medicine ,Platelet ,Thromboxane-A synthase ,Antagonism ,Receptor ,Molecular Biology - Abstract
(3-Pyridinyl)alkanoic acids substituted at the 4-position with an (arylsulfonamido)alkyl group were synthesized and found to behave as platelet thromboxane receptor antagonists (TxRAs) and thromboxane synthase inhibitors (TxSIs). The compounds behaved as agonists at the vascular receptor for thromboxane A2.
- Published
- 1992
24. Thromboxane receptor antagonism combined with thromboxane synthase inhibition. 7. pyridinylalkyl-substituted arylsulfonylamino arylalkanoic acids
- Author
-
J. Mathis, Robert Goldstein, Main Alan J, K. Grim, Candido Gude, David Cohen, W. Lee, Ronald Dotson, Shripad S. Bhagwat, and D.M. Roland
- Subjects
biology ,Stereochemistry ,Chemistry ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Bioavailability ,Thromboxane receptor ,Platelet inhibitor ,Drug Discovery ,biology.protein ,Molecular Medicine ,Thromboxane-A synthase ,Antagonism ,Molecular Biology - Abstract
Arylsulfonylamino arylalkanoic acids substituted with a pyridinylalkyl group on the arylalkanoic acid portion of the molecule were synthesized and found to behave as thromboxane receptor antagonists (TxRAs) and thromboxane synthase inhibitors (TxSIs). One of these compounds (11), with a 1,3,5-trisubstituted central aromatic ring was demonstrated to have good functional bioavailability and efficacy as a platelet inhibitor in guinea pigs.
- Published
- 1992
25. Thromboxane receptor antagonism combined with thromboxane synthase inhibition. 3. Pyridinylalkyl-substituted 8-[(arylsulfonyl)amino]octanoic acids
- Author
-
Main Alan J, David Cohen, Patricia Furness, Marissa Louzan, Shripad S. Bhagwat, Clay Boswell, Robert Goldstein, Warren Lee, and Candido Gude
- Subjects
Platelet Aggregation ,Pyridines ,Stereochemistry ,Receptors, Thromboxane ,Thromboxane receptor ,Structure-Activity Relationship ,Thromboxane A2 ,chemistry.chemical_compound ,Dogs ,Biosynthesis ,Drug Discovery ,Animals ,Humans ,Vasoconstrictor Agents ,Structure–activity relationship ,biology ,Muscle, Smooth ,Biological activity ,Prostaglandin Endoperoxides, Synthetic ,Biochemistry ,chemistry ,Enzyme inhibitor ,15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid ,biology.protein ,Molecular Medicine ,Platelet aggregation inhibitor ,Thromboxane-A Synthase ,Thromboxane-A synthase ,Caprylates ,Platelet Aggregation Inhibitors - Abstract
A series of 8-[(arylsulfonyl)amino]octanoic acids substituted with a pyridinylalkyl group along the chain were synthesized and tested in vitro for their ability to both antagonize the binding of thromboxane A2 to its receptors and to inhibit the thromboxane synthase enzyme. This series of compounds were found to inhibit the U 46619-induced aggregation of human platelets and the U 46619-induced contraction of dog saphenous vein. The compounds also inhibited TxA2 biosynthesis in a human microsomal platelet preparation. The relative position of the pyridinylalkyl and arylsulfonamide groups had significant effects on the thromboxane receptor antagonist (TxRA) activity and thromboxane synthase inhibitor (TxSI) activity. Compounds with the pyridine ring at the 7- or 8-position of the octanoic acid side chain were weakly active as TxSI but behaved as potent TxRA at the platelet receptor for TxA2. However, these compounds were agonists at the vascular receptor. Substitution of the pyridinylalkyl group at the 2- or 3-position resulted in compounds with potent TxSI activity and weak TxRA activity. The activity profile of the compounds with the pyridinylalkyl substitution at the 4-, 5-, or 6-position was very desirable. Compound 22 with a pyridinylpropyl substituent at the 4-position was found to display extremely potent TxRA and TxSI properties.
- Published
- 1992
26. Thromboxane receptor antagonism combined with thromboxane synthase inhibition. 4. 8-[[(4-Chlorophenyl)sulfonyl]amino]-4-[3-(3-pyridinyl)propyl]octanoic acid and analogs
- Author
-
Warren Lee, J. Mathis, Clay Boswell, Shripad S. Bhagwat, Nicolina Contardo, Ronald Dotson, Patricia Furness, Candido Gude, David Cohen, and Harry Zoganas
- Subjects
Male ,Platelet Aggregation ,Pyridines ,Bronchoconstriction ,Guinea Pigs ,Receptors, Thromboxane ,Thromboxane receptor ,Structure-Activity Relationship ,Thromboxane A2 ,chemistry.chemical_compound ,Dogs ,In vivo ,Drug Discovery ,Animals ,Humans ,Vasoconstrictor Agents ,Sulfonamides ,biology ,Biological activity ,Prostaglandin Endoperoxides, Synthetic ,chemistry ,Biochemistry ,Enzyme inhibitor ,15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid ,biology.protein ,Molecular Medicine ,Arachidonic acid ,Thromboxane-A Synthase ,Thromboxane-A synthase ,Caprylates ,Antagonism ,Platelet Aggregation Inhibitors - Abstract
The title compound (10a) and its analogs were synthesized and found to possess two activities, the inhibition of the biosynthesis of thromboxane A2 and antagonism of its receptors. The in vitro and in vivo profile of these compounds as thromboxane receptor antagonists (TxRAs) and thromboxane synthase inhibitors (TxSIs) is described. 10a and its analogs displayed very potent TxRA activity in human washed platelets (IC50 approximately 10(-7)-10(-9) M) and dog saphenous vein (pA2 approximately 9) and also potent TxSI activity (IC50 approximately 10(-9) M). The good bioavailability and the long duration of action of some of these compounds was demonstrated using ex vivo measurement of the TxRA activity upon oral administration to guinea pigs. Compounds 10a, 20, and 33 potently inhibited arachidonic acid induced bronchoconstriction in guinea pigs.
- Published
- 1992
27. Identification of N-(5-tert-butyl-isoxazol-3-yl)-N'-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea dihydrochloride (AC220), a uniquely potent, selective, and efficacious FMS-like tyrosine kinase-3 (FLT3) inhibitor
- Author
-
Qi, Chao, Kelly G, Sprankle, Robert M, Grotzfeld, Andiliy G, Lai, Todd A, Carter, Anne Marie, Velasco, Ruwanthi N, Gunawardane, Merryl D, Cramer, Michael F, Gardner, Joyce, James, Patrick P, Zarrinkar, Hitesh K, Patel, and Shripad S, Bhagwat
- Subjects
Male ,Phenylurea Compounds ,Drug Evaluation, Preclinical ,Xenograft Model Antitumor Assays ,Rats ,Substrate Specificity ,Mice ,Solubility ,fms-Like Tyrosine Kinase 3 ,Cell Line, Tumor ,Animals ,Humans ,Female ,Benzothiazoles ,Protein Kinase Inhibitors - Abstract
Treatment of AML patients with small molecule inhibitors of FLT3 kinase has been explored as a viable therapy. However, these agents are found to be less than optimal for the treatment of AML because of lack of sufficient potency or suboptimal oral pharmacokinetics (PK) or lack of adequate tolerability at efficacious doses. We have developed a series of extremely potent and highly selective FLT3 inhibitors with good oral PK properties. The first series of compounds represented by 1 (AB530) was found to be a potent and selective FLT3 kinase inhibitor with good PK properties. The aqueous solubility and oral PK properties at higher doses in rodents were found to be less than optimal for clinical development. A novel series of compounds were designed lacking the carboxamide group of 1 with an added water solubilizing group. Compound 7 (AC220) was identified from this series to be the most potent and selective FLT3 inhibitor with good pharmaceutical properties, excellent PK profile, and superior efficacy and tolerability in tumor xenograft models. Compound 7 has demonstrated a desirable safety and PK profile in humans and is currently in phase II clinical trials.
- Published
- 2009
28. Crystal structures of human adenosine kinase inhibitor complexes reveal two distinct binding modes
- Author
-
Clarissa L. Jakob, Chih-Hung Lee, Haixia Yu, Elizabeth A. Kowaluk, Shripad S. Bhagwat, Richard A. Smith, Mark A. Matulenko, Jean M. Severin, Andrew O. Stewart, Michael F. Jarvis, Arthur Gomtsyan, Marlon D. Cowart, and Steven W. Muchmore
- Subjects
Adenosine monophosphate ,Models, Molecular ,Stereochemistry ,Protein Conformation ,Morpholines ,Adenosine kinase ,Crystallography, X-Ray ,Tubercidin ,chemistry.chemical_compound ,Drug Discovery ,medicine ,Animals ,Humans ,Binding site ,Enzyme Inhibitors ,Adenosine Kinase ,chemistry.chemical_classification ,Antiinfective agent ,Binding Sites ,biology ,Molecular Structure ,Adenosine ,Enzyme ,Pyrimidines ,chemistry ,Cyclic nucleotide-binding domain ,biology.protein ,Molecular Medicine ,Adenosine triphosphate ,Toxoplasma ,medicine.drug ,Protein Binding - Abstract
Adenosine kinase (AK) is an enzyme responsible for converting endogenous adenosine (ADO) to adenosine monophosphate (AMP) in an adenosine triphosphate- (ATP-) dependent manner. The structure of AK consists of two domains, the first a large alpha/beta Rossmann-like nucleotide binding domain that forms the ATP binding site, and a smaller mixed alpha/beta domain, which, in combination with the larger domain, forms the ADO binding site and the site of phosphoryl transfer. AK inhibitors have been under investigation as antinociceptive, antiinflammatory, and anticonvulsant as well as antiinfective agents. In this work, we report the structures of AK in complex with two classes of inhibitors: the first, ADO-like, and the second, a novel alkynylpyrimidine series. The two classes of structures, which contain structurally similar substituents, reveal distinct binding modes in which the AK structure accommodates the inhibitor classes by a 30 degrees rotation of the small domain relative to the large domain. This change in binding mode stabilizes an open and a closed intermediate structural state and provide structural insight into the transition required for catalysis. This results in a significant rearrangement of both the protein active site and the orientation of the alkynylpyrimidine ligand when compared to the observed orientation of nucleosidic inhibitors or substrates.
- Published
- 2006
29. Novel orally available brain penetrant small molecule inhibitors of ganglioside biosynthesis for the treatment of Sandhoff and Tay–Sachs diseases
- Author
-
Hong Sun, Brett E. Crawford, Xiaomei Bai, Lan Tang, Shripad S. Bhagwat, and Sergio G. Durón
- Subjects
chemistry.chemical_compound ,Endocrinology ,chemistry ,Biochemistry ,Endocrinology, Diabetes and Metabolism ,Genetics ,Ganglioside biosynthesis ,Penetrant (biochemical) ,Molecular Biology ,Small molecule - Published
- 2013
30. Synthesis and Biological Evaluation of Pteridine and Pyrazolopyrimidine Based Adenosine Kinase Inhibitors
- Author
-
Arthur Gomtsyan, Michael F. Jarvis, Elizabeth A. Kowaluk, Shripad S. Bhagwat, Chih-Hung Lee, Andrew O. Stewart, and Stanley Didomenico
- Subjects
Pteridine derivatives ,biology ,General Medicine ,Adenosine kinase ,Pyrazolopyrimidine ,chemistry.chemical_compound ,chemistry ,Biochemistry ,medicine ,biology.protein ,IC50 ,Pteridine ,medicine.drug ,Biological evaluation - Abstract
Three new approaches have been tested to modify existing pyridopyrimidine and alkynylpyrimidine classes of nonnucleoside adenosine kinase inhibitors 2 and 3. 4-Amino-substituted pteridines 8a–e were generally less active than corresponding 5- and 6-substituted pyridopyrimidines 2. Pyrazolopyrimidine 13c with IC50=7.5 nM was superior to its open chain alkynylpyrimidine analog 13g (IC50=22 nM) while pyrrolopyrimidines such as 17a were inactive.
- Published
- 2004
31. Synthesis and biological evaluation of pteridine and pyrazolopyrimidine based adenosine kinase inhibitors
- Author
-
Shripad S. Bhagwat, Michael F. Jarvis, Arthur Gomtsyan, Chih-Hung Lee, Andrew O. Stewart, Elizabeth A. Kowaluk, and Stanley Didomenico
- Subjects
Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Adenosine kinase ,Biochemistry ,Chemical synthesis ,Pyrazolopyrimidine ,chemistry.chemical_compound ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Enzyme Inhibitors ,Molecular Biology ,IC50 ,Adenosine Kinase ,chemistry.chemical_classification ,biology ,Bicyclic molecule ,Chemistry ,Pteridines ,Organic Chemistry ,Enzyme ,Pyrimidines ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,Pyrazoles ,Pteridine ,medicine.drug - Abstract
Three new approaches have been tested to modify existing pyridopyrimidine and alkynylpyrimidine classes of nonnucleoside adenosine kinase inhibitors 2 and 3. 4-Amino-substituted pteridines 8a–e were generally less active than corresponding 5- and 6-substituted pyridopyrimidines 2. Pyrazolopyrimidine 13c with IC50=7.5 nM was superior to its open chain alkynylpyrimidine analog 13g (IC50=22 nM) while pyrrolopyrimidines such as 17a were inactive.
- Published
- 2004
32. 5,6,7-trisubstituted 4-aminopyrido[2,3-d]pyrimidines as novel inhibitors of adenosine kinase
- Author
-
Erol K. Bayburt, Jeffery A. McKie, Joe Mikusa, Shripad S. Bhagwat, Elizabeth A. Kowaluk, Chih-Hung Lee, Karen M. Alexander, Richard J. Perner, Michael F. Jarvis, Gu Yu-Gui, Kathy L. Kohlhaas, and Carol T. Wismer
- Subjects
Stereochemistry ,Pyridines ,Adenosine kinase ,Chemical synthesis ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,In vivo ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,Phosphorylation ,Adenosine Kinase ,Pain Measurement ,chemistry.chemical_classification ,Analgesics ,biology ,Bicyclic molecule ,Aryl ,In vitro ,Rats ,Enzyme ,Pyrimidines ,chemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine - Abstract
The synthesis and structure-activity relationship of a series of 5,6,7-trisubstituted 4-aminopyrido[2,3-d]pyrimidines as novel nonnucleoside adenosine kinase inhibitors is described. A variety of alkyl, aryl, and heteroaryl substituents were found to be tolerated at the C5, C6, and C7 positions of the pyridopyrimidine core. These studies have led to the identification of analogues that are potent inhibitors of adenosine kinase with in vivo analgesic activity.
- Published
- 2003
33. Synthesis and structure-activity relationships of 5-heteroatom-substituted pyridopyrimidines as adenosine kinase inhibitors
- Author
-
Arthur Gomtsyan, Erol K. Bayburt, Stanley Didomenico, Andrew O. Stewart, Michael F. Jarvis, Marlon D. Cowart, Elizabeth A. Kowaluk, Gregory A. Gfesser, Chih Hung Lee, and Shripad S. Bhagwat
- Subjects
Magnetic Resonance Spectroscopy ,Adenosine kinase ,Chemical synthesis ,Structure-Activity Relationship ,In vivo ,Heterocyclic Compounds ,Drug Discovery ,medicine ,Extracellular ,Structure–activity relationship ,Enzyme Inhibitors ,Adenosine Kinase ,Pharmacology ,chemistry.chemical_classification ,biology ,Chemistry ,Organic Chemistry ,General Medicine ,Adenosine ,In vitro ,Enzyme ,Pyrimidines ,Biochemistry ,Solubility ,Enzyme inhibitor ,Hyperalgesia ,biology.protein ,Biophysics ,Indicators and Reagents ,medicine.symptom ,Intracellular ,medicine.drug - Abstract
Under stressful conditions, many cells release adenosine to minimize tissue damage. Inhibition of intracellular adenosine kinase (AK) increases the local extracellular concentration of adenosine and its effect on traumatized tissue. The synthesis and SAR of a new series of pyridopyrimidines for the inhibition of AK are described. It was found that a range of analogs with position five substituted by an amine or ether functionality increased aqueous solubility while retaining the in vitro potency of initial leads. A narrower range of analogs was active in vivo in a rat inflammatory hyperalgesia model.
- Published
- 2003
34. Design, synthesis, and structure-activity relationship of 6-alkynylpyrimidines as potent adenosine kinase inhibitors
- Author
-
Haixia Yu, Mark A. Matulenko, Stanley Didomenico, Chih-Hung Lee, Joe Mikusa, Ki H. Kim, Kathy L. Kohlhaas, Shripad S. Bhagwat, Arthur Gomtsyan, Elizabeth A. Kowaluk, Carol T. Wismer, and Michael F. Jarvis
- Subjects
Models, Molecular ,Adenosine ,Magnetic Resonance Spectroscopy ,Pyridines ,Morpholines ,Anti-Inflammatory Agents ,Inflammation ,Adenosine kinase ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Extracellular ,Tumor Cells, Cultured ,Structure–activity relationship ,Animals ,Humans ,Enzyme Inhibitors ,Phosphorylation ,Adenosine Kinase ,Pain Measurement ,chemistry.chemical_classification ,Analgesics ,biology ,Chemistry ,In vitro ,Rats ,Enzyme ,Pyrimidines ,Biochemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,medicine.symptom ,medicine.drug - Abstract
Adenosine (ADO) is an extracellular signaling molecule within the central and peripheral nervous system. Its concentration is increased at sites of tissue injury and inflammation. One of the mechanisms by which antinociceptive and antiinflammatory effects of ADO can be enhanced consists of inhibition of adenosine kinase (AK), the primary metabolic enzyme for ADO. Novel nonnucleoside AK inhibitors based on 4-amino-6-alkynylpyrimidines were prepared, and the importance of the length of the linker at the 5-position for high affinity AK inhibition was demonstrated. Compounds with 2- and 3-atom linkers were the most potent AK inhibitors. Optimization of their physicochemical properties led to 31a and 37a that effectively reduced pain and inflammation in animal models.
- Published
- 2002
35. Effects of SP500263, a novel, potent antiestrogen, on breast cancer cells and in xenograft models
- Author
-
Helen, Brady, Sonal, Desai, Leah M, Gayo-Fung, Sak, Khammungkhune, Jeffrey A, McKie, Eoin, O'Leary, Laura, Pascasio, May Kung, Sutherland, David W, Anderson, Shripad S, Bhagwat, and Bernd, Stein
- Subjects
Selective Estrogen Receptor Modulators ,Transplantation, Heterologous ,Mammary Neoplasms, Experimental ,Mice, Nude ,Breast Neoplasms ,Mice ,Estrogen Receptor Modulators ,Piperidines ,Coumarins ,Tumor Cells, Cultured ,Animals ,Humans ,Female ,Neoplasm Transplantation - Abstract
We have compared the antitumor activities of SP500263, a novel next-generation selective estrogen receptor modulator (SERM), tamoxifen, and raloxifene side-by-side in in vitro and in vivo MCF-7 breast cancer models. In vitro, SP500263 acted as an antiestrogen and potently inhibited estrogen-dependent MCF-7 proliferation with IC(50) values in the nanomolar range. SP500263 also strongly inhibited MCF-7 proliferation in the absence of estrogen at all of the concentrations tested. To investigate the antitumor activity of SP500263 in animals, athymic nude mice were implanted with MCF-7 tumor in the presence of a tumor growth-supporting sustained release estrogen pellet. Treatment was initiated after tumors were established. SP500263, administered for 28 days through daily i.p. dosing, effectively reduced estrogen-stimulated tumor growth at 3 and 30 mg/kg. SP500263 was as efficacious as tamoxifen and superior to raloxifene at the corresponding doses. Maximum efficacy was reached with the 30 mg/kg dose. The observed effects were highly significant. SP500263 represents a member of a novel series of SERMs that is structurally unrelated to SERMs currently on the market or in clinical development. The experiments described herein demonstrate that SP500263 is efficacious in the MCF-7 proliferation assay and in a murine model of breast cancer.
- Published
- 2002
36. Lead identification of a potent benzopyranone selective estrogen receptor modulator
- Author
-
Adam Kois, Normand Richard, Khammungkhune Sak, Graziella I. Shevlin, Shripad S. Bhagwat, John Sapienza, Helen Brady, Mathew Hickman, Jalluri Ravi Kumar, Deborah Mortensen, Gayo Leah M, Jeffrey A. Mckie, Mary Doubleday, May S Kung Sutherland, and Bernd Stein
- Subjects
Clinical Biochemistry ,Cell ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,chemistry.chemical_compound ,Estrogen Receptor Modulators ,Piperidines ,Coumarins ,Drug Discovery ,medicine ,Tumor Cells, Cultured ,Animals ,Raloxifene ,Molecular Biology ,Binding Sites ,Estradiol ,Molecular Structure ,Chemistry ,Interleukin-6 ,Organic Chemistry ,Estrogen Antagonists ,Estrogen Receptor alpha ,Ligand (biochemistry) ,In vitro ,Tamoxifen ,medicine.anatomical_structure ,Selective estrogen receptor modulator ,Raloxifene Hydrochloride ,Molecular Medicine ,Female ,Estrogen receptor alpha ,Lead compound ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
Starting from a phenol screening hit (6), three series of benzopyranone selective estrogen receptor modulators (SERMs) have been designed, synthesized, and analyzed for both estrogen receptor alpha binding affinity and in vitro activity in two cell assays. The lead compound identified, SP500263 (13), was more potent than raloxifene and tamoxifen in a cell-based assay measuring inhibition of interleukin-6 release.
- Published
- 2002
37. SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase
- Author
-
Aparna Motiwala, Steve Pierce, Yoshitaka Satoh, Jim C. Leisten, Dennis T. Sasaki, Shripad S. Bhagwat, Eoin C. O'leary, Steve T. Sakata, Brydon L. Bennett, Brion W. Murray, David W. Anderson, Anthony M. Manning, and Weiming Xu
- Subjects
CD4-Positive T-Lymphocytes ,Gene Expression ,Anthraquinones ,Lymphocyte Activation ,Binding, Competitive ,Monocytes ,Proinflammatory cytokine ,Jurkat Cells ,Mice ,Structure-Activity Relationship ,Adenosine Triphosphate ,Animals ,Humans ,Enzyme Inhibitors ,Pyrazolones ,Protein kinase A ,Protein Kinase Inhibitors ,Cells, Cultured ,Anthracenes ,Multidisciplinary ,biology ,MAP kinase kinase kinase ,Molecular Structure ,Kinase ,Tumor Necrosis Factor-alpha ,JNK Mitogen-Activated Protein Kinases ,Cell Differentiation ,Biological Sciences ,Molecular biology ,Mice, Inbred C57BL ,c-Jun N-terminal kinases ,Apoptosis ,biology.protein ,Phosphorylation ,Cytokines ,Pyrazoles ,Tumor necrosis factor alpha ,Female ,Mitogen-Activated Protein Kinases - Abstract
Jun N-terminal kinase (JNK) is a stress-activated protein kinase that can be induced by inflammatory cytokines, bacterial endotoxin, osmotic shock, UV radiation, and hypoxia. We report the identification of an anthrapyrazolone series with significant inhibition of JNK1, -2, and -3 (Ki= 0.19 μM). SP600125 is a reversible ATP-competitive inhibitor with >20-fold selectivity vs. a range of kinases and enzymes tested. In cells, SP600125 dose dependently inhibited the phosphorylation of c-Jun, the expression of inflammatory genesCOX-2,IL-2,IFN-γ,TNF-α, and prevented the activation and differentiation of primary human CD4 cell cultures. In animal studies, SP600125 blocked (bacterial) lipopolysaccharide-induced expression of tumor necrosis factor-α and inhibited anti-CD3-induced apoptosis of CD4+CD8+thymocytes. Our study supports targeting JNK as an important strategy in inflammatory disease, apoptotic cell death, and cancer.
- Published
- 2001
38. Pyridopyrimidine analogues as novel adenosine kinase inhibitors
- Author
-
John R. Koenig, Elizabeth A. Kowaluk, Karen M. Alexander, Andrew O. Stewart, Guo Zhu Zheng, Carol T. Wismer, Michael F. Jarvis, Yui Mao, Katharine L. Chu, Mark A. Matulenko, Richard J. Perner, Steve Muchmore, Ki H. Kim, Mei Qun Jiang, Kennan C. Marsh, Chih-Hung Lee, Haixia Yu, Shripad S. Bhagwat, Joseph P. Mikusa, John K. Pratt, Kathy L. Kohlhaas, Steve McGaraughty, and Arthur Gomtsyan
- Subjects
Models, Molecular ,Stereochemistry ,Morpholines ,Clinical Biochemistry ,Molecular Conformation ,Pharmaceutical Science ,Adenosine kinase ,Biochemistry ,Chemical synthesis ,Structure-Activity Relationship ,In vivo ,Drug Discovery ,Moiety ,Enzyme Inhibitors ,Molecular Biology ,Adenosine Kinase ,chemistry.chemical_classification ,biology ,Bicyclic molecule ,Organic Chemistry ,In vitro ,Enzyme ,Pyrimidines ,chemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine - Abstract
A novel series of pyridopyrimidine analogues 9 was identified as potent adenosine kinase inhibitors based on the SAR and computational studies. Substitution of the C7 position of the pyridopyrimidino core with C2' substituted pyridino moiety increased the in vivo potency and enhanced oral bioavailability of these adenosine kinase inhibitors.
- Published
- 2001
39. Structure-activity studies of 5-substituted pyridopyrimidines as adenosine kinase inhibitors
- Author
-
Haixia Yu, Karen M. Alexander, Erol K. Bayburt, Chih-Hung Lee, Elizabeth A. Kowaluk, Gregory A. Gfesser, Carol T. Wismer, Andrew O. Stewart, Kathy L. Kohlhaas, Steve McGaraughty, Joseph P. Mikusa, Shripad S. Bhagwat, Chang Zhu, Marlon D. Cowart, and Michael F. Jarvis
- Subjects
Cell Membrane Permeability ,Tertiary amine ,Clinical Biochemistry ,Pharmaceutical Science ,Administration, Oral ,Pain ,Adenosine kinase ,Biochemistry ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Structure–activity relationship ,Animals ,Enzyme Inhibitors ,Molecular Biology ,Adenosine Kinase ,Pain Measurement ,chemistry.chemical_classification ,biology ,Molecular Structure ,Chemistry ,Organic Chemistry ,Adenosine ,Rats ,Enzyme ,Pyrimidines ,Enzyme inhibitor ,Hyperalgesia ,biology.protein ,Molecular Medicine ,Phosphorylation ,medicine.symptom ,medicine.drug - Abstract
The synthesis and SAR of a novel series of non-nucleoside pyridopyrimidine inhibitors of the enzyme adenosine kinase (AK) are described. It was found that pyridopyrimidines with a broad range of medium and large non-polar substituents at the 5-position potently inhibited AK activity. A narrower range of analogues was capable of potently inhibiting adenosine phosphorylation in intact cells indicating an enhanced ability of these analogues to penetrate cell membranes. Potent AK inhibitors were found to effectively reduce nociception in animal models of thermal hyperalgesia and persistent pain.
- Published
- 2001
40. Gene-regulating protein kinases as important anti-inflammatory targets
- Author
-
Alan J Lewis, Anthony M. Manning, Merl F. Hoekstra, and Shripad S. Bhagwat
- Subjects
Pharmacology ,Drug discovery ,Kinase ,Biology ,medicine.disease_cause ,Cell biology ,Biochemistry ,Drug Discovery ,Protein targeting ,medicine ,Phosphorylation ,Protein phosphorylation ,Signal transduction ,Protein kinase A ,Transcription factor - Abstract
Protein phosphorylation is a key cellular regulatory mechanism. Protein kinases and phosphatases regulate cell-cycle progression, transcription, translation, protein sorting and cell adhesion events that are critical to the inflammatory process. Two of the best- characterized immunosuppressants, cyclosporin and rapamycin, are also effective anti-inflammatory drugs. They act directly on protein phosphorylation and, as such, validate the concept that small-molecule modulators of phosphorylation cascades possess anti- inflammatory properties. The authors describe studies that outline progress in defining specific protein kinase signal-transduction cascades, the key drug discovery targets in these cascades and progress towards developing selective agents that have potential in treating numerous inflammatory diseases.
- Published
- 1999
41. Dual inhibition of angiotensin converting enzyme and neutral endopeptidase 24.11
- Author
-
Shripad S. Bhagwat
- Subjects
chemistry.chemical_classification ,Metalloproteinase ,Dipeptide ,biology ,Stereochemistry ,fungi ,Active site ,Angiotensin-converting enzyme ,Angiotensin II ,chemistry.chemical_compound ,Biochemistry ,chemistry ,Renin–angiotensin system ,biology.protein ,Glycoprotein ,Neprilysin - Abstract
Publisher Summary This chapter presents an overview of different approaches leading to the discovery of dual angiotensin converting enzyme and neutral endopeptidase (ACE/NEP) inhibitors. ACE is a membrane bound glycoprotein, which plays a major role in the renin-angiotensin-aldosterone system by cleaving the C-terminal dipeptide portion (His-Leu) of angiotensin I (AI) to produce angiotensin II (AII) which is a potent vasoconstrictor. On the other hand, neutral endopeptidase is a 90 kDa membrane bound glycoprotein, which hydrolyzes peptides at the amino group of hydrophobic residues. Design of novel compounds which inhibits both ACE and NEP has been facilitated by examination of the structural features of the selective ACE and selective NEP inhibitors. ACE and NEP are both zinc metalloproteases with one zinc atom in their active site. The thiol group seems to be a good functional group to incorporate in the design of dual ACE/NEP inhibitors as it binds to zinc ion with high affinity.
- Published
- 1997
42. Small molecule inhibitors of glycosaminoglycan biosynthesis as substrate optimization therapy for the mucopolysaccharidoses
- Author
-
Jillian R. Brown, Rob W. Herman, Katherine A. Webster, Shripad S. Bhagwat, and Brett E. Crawford
- Subjects
Endocrinology ,Endocrinology, Diabetes and Metabolism ,Genetics ,Molecular Biology ,Biochemistry - Published
- 2013
43. Chapter 3. P2 Purinoceptors: A Family of Novel Therapeutic Targets
- Author
-
Michael Williams and Shripad S. Bhagwat
- Subjects
Allosteric regulation ,Purinergic receptor ,Pharmacology ,Biology ,Adenosine ,chemistry.chemical_compound ,chemistry ,medicine ,Pharmacophore ,Receptor ,Adenosine triphosphate ,Adenosine A2B receptor ,medicine.drug ,Uridine triphosphate - Abstract
Publisher Summary This chapter discusses the identification of specific ligands, agonists, antagonists, and allosteric modulators to define the physiological/pharmacological function of P 2 purinoceptors. Purinoceptors have been originally divided into P 1 (ADO) and P 2 (adenosine triphosphate; ATP) subclasses. Pharmacological evaluation led to the classification of P 2X and P 2Y classes with the addition of P 2T and P 2Z receptors. Adenosine triphosphate (ATP) is an unusual candidate for a neurotransmitter, this role being conceptually viewed as an unorthodox use of cellular energy stores. As well as interacting with the members of the P 2 receptor family, ATP can be broken down via synaptic ectonucleotidase action to form adenosine (ADO), a neuromodulator in its own right. ATP can also modulate ADO interactions at the A 1 receptor. P 2 receptor nomenclature is currently in a state of considerable flux, evolving from a pharmacological basis to the state that relates receptor cloning to function. From a drug discovery perspective, it is a major step from the cloning and expression of the members of a new receptor family to defining their function. All known agonist ligands for the P 2 receptor family are variations on the purine nucleotide pharmacophore. The identification of novel pharmacophores selective for P 2 receptors that can be used to unambiguously characterize the various members of the receptor superfamily is critical to advancing the field. The P 2 receptor legands are potential of different therapeutic use. ATP is an effective and long-lasting inhibitor of human tumor cell growth. Again, ATP can be used as an adjunct to inhalation anesthetics. ATP and uridine triphosphate (UTP) have been evaluated as treatments for cystic fibrosis. P 2 receptor mechanisms may also be involved in cell adhesion. Thus, P 2 purinoceptors remains a key element in the discovery of new therapeutic agents.
- Published
- 1996
44. Abstract 2934: Novel approach for treating neural crest derived tumors: Selective inhibition of ganglioside biosynthesis with small molecules
- Author
-
Brett E. Crawford, Charles A. Glass, Xiaomei Bai, Shripad S. Bhagwat, Jillian R. Brown, Tram Nguyen, and Sergio G. Durón
- Subjects
Cancer Research ,Glycan ,Ganglioside ,Melanoma ,Growth factor ,medicine.medical_treatment ,Neural crest ,Biology ,medicine.disease ,Glycolipid ,Oncology ,Biochemistry ,Cell culture ,medicine ,biology.protein ,Cancer research ,Lipid raft - Abstract
Neural crest derived tumors express high levels of a unique class of lipid linked glycan known as gangliosides. Gangliosides are involved in growth factor signaling by regulating complexes in lipid rafts. Genetic studies show that through aberrant expression of gangliosides, these tumors acquire aggressive growth properties. Prior to this research, the only ganglioside inhibitors identified were non-specific and broadly blocked virtually all glycolipid classes. These non-specific glycolipid inhibitors demonstrated anti-cancer activity in animal models of neural crest tumors. However, due to substantial off-target dose-limiting toxicity from lack of specificity for the ganglioside sub-class, they effectively cannot be used in humans for cancer treatment. Selective inhibition of gangliosides without affecting other glycan classes could potentially avoid these problems and provide an effective treatment for neural crest and other ganglioside-dependent tumors. To identify the first known selective inhibitors of gangliosides, we developed a novel molecular screening strategy for identifying selective small-molecule ganglioside inhibitors. This platform identified the first drug-like selective inhibitors of gangliosides. ZP10395, a lead compound, selectively and dose-dependently reduces gangliosides in multiple tumor cell lines and is 10-15 fold more potent than the existing non-specific inhibitors. Importantly, it does not inhibit other glycolipid classes associated with dose-limiting toxicity. Administering ZP10395 to a mouse xenograph melanoma model significantly reduced ganglioside production and slowed tumor growth in the presence of a reduced T-cell response. These results demonstrate the potential utility of specific ganglioside inhibitors for treating ganglioside dependent tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2934. doi:10.1158/1538-7445.AM2011-2934
- Published
- 2011
45. Thromboxane receptor antagonism combined with thromboxane synthase inhibition. 5. Synthesis and evaluation of enantiomers of 8-[[(4-chlorophenyl)sulfonyl]amino]-4-(3-pyridinylalkyl)octanoic acid
- Author
-
Candido Gude, J. Mathis, David Cohen, Shripad S. Bhagwat, Patricia Furness, Ron Dotson, and Warren Lee
- Subjects
Platelet Aggregation ,Stereochemistry ,Thromboxane ,Pyridines ,Carboxylic acid ,Guinea Pigs ,Receptors, Thromboxane ,Ether ,Thromboxane receptor ,chemistry.chemical_compound ,Structure-Activity Relationship ,Drug Discovery ,Animals ,Humans ,Vasoconstrictor Agents ,chemistry.chemical_classification ,Sulfonyl ,Sulfonamides ,biology ,Stereoisomerism ,Sulfonamide ,Prostaglandin Endoperoxides, Synthetic ,chemistry ,15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid ,biology.protein ,Molecular Medicine ,Thromboxane-A synthase ,Thromboxane-A Synthase ,Enantiomer ,Caprylates - Abstract
The enantiomers of 8-[[(4-chlorophenyl)sulfonyl]amino]-4-(3-pyridinylpropyl)octanoic acid (1) and its pyridinyl ether analog (2) were synthesized using the highly diastereoselective method of alkylation of acyloxazolidinone. These enantiomerically pure compounds were compared with the corresponding racemic compounds 1 and 2 for their in vitro activity. Compounds 1, 1R, and 1S and 2,2S, and 2R were equipotent as thromboxane receptor antagonists (TxRAs) and thromboxane synthase inhibitors (TxSIs) (IC50 = 2-30 nM). Upon oral administration to guinea pigs, the enantiomers inhibited the ex vivo U 46619-induced platelet aggregation with potency similar to that of the corresponding racemic compound. This indicates that the enantiomers have pharmacologic profile and bioavailability similar to that of the corresponding racemic compound.
- Published
- 1993
46. Thromboxane receptor antagonism combined with thromboxane synthase inhibition. 1. (+/-)-(3-pyridinylbicycloheptyl)alkanoic acids
- Author
-
Candido Gude, Warren Lee, Frank H Clarke, Patricia Furness, Shripad S. Bhagwat, and David Cohen
- Subjects
Blood Platelets ,Models, Molecular ,Thromboxane ,Pyridines ,Receptors, Prostaglandin ,Receptors, Thromboxane ,Carboxylic Acids ,In Vitro Techniques ,Thromboxane receptor ,Thromboxane A2 ,chemistry.chemical_compound ,Bridged Bicyclo Compounds ,X-Ray Diffraction ,Microsomes ,Drug Discovery ,Humans ,Platelet ,Receptor ,biology ,Chemistry ,Thromboxanes ,Biological activity ,Biochemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,Thromboxane-A synthase ,Thromboxane-A Synthase - Abstract
The design, synthesis, and in vitro pharmacology of a new class of compounds exerting both thromboxane receptor antagonist and thromboxane synthase inhibitory activities is described. [(3-Pyridinyl)bicycloheptyl] alkanoic acid 9 and its analogues, designed with the help of molecular modeling, were synthesized and found to be inhibitors of thromboxane A2 (TxA2) biosynthesis in a human platelet microsomal preparation. The compounds were also found to antagonize both platelet and vascular TxA2 receptors. The compounds inhibited the U 46619 induced aggregation of human washed platelets and platelet-rich plasma and the U 46619 induced contraction of the dog saphenous vein.
- Published
- 1991
47. Purinergic Approaches in Experimental Therapeutics Edited by Kenneth A. Jacobson and Michael F. Jarvis. Wiley-Liss, New York. 1997. xiv + 581 pp. 16 × 24 cm. ISBN 0-47114071-6. $89.95
- Author
-
Shripad S. Bhagwat
- Subjects
Chemistry ,Drug Discovery ,Purinergic receptor ,Molecular Medicine ,Theology - Published
- 1998
48. The P2 Nucleotide Receptors Edited by John T. Turner, Gary A. Weisman, and Jeffrey S. Fedan. Humana Press, Totowa, NJ. 1997. xi + 440 pp. 16 × 23.5 cm. ISBN 0-89603-425-9. $139.00
- Author
-
Shripad S. Bhagwat
- Subjects
Chemistry ,Drug Discovery ,Molecular Medicine ,Theology ,Receptor - Published
- 1998
49. Synthesis of thromboxane A2
- Author
-
W. Clark Still, Shripad S. Bhagwat, and Philip R. Hamann
- Subjects
biology ,Bicyclic molecule ,Stereochemistry ,General Chemistry ,Biochemistry ,Catalysis ,Thromboxane B2 ,chemistry.chemical_compound ,Thromboxane A2 ,Colloid and Surface Chemistry ,chemistry ,biology.protein ,Organic chemistry ,Thromboxane-A synthase ,Aliphatic compound - Published
- 1985
50. Preparation of the 2,6-dioxa[3.1.1]Bicycloheptane nucleus of thromboxane A2
- Author
-
Philip R. Hamann, W. Clark Still, and Shripad S. Bhagwat
- Subjects
Bicyclic molecule ,Stereochemistry ,Organic Chemistry ,Acetal ,Diol ,Biochemistry ,chemistry.chemical_compound ,Thromboxane A2 ,Hydrolysis ,medicine.anatomical_structure ,chemistry ,Drug Discovery ,medicine ,Chemical reduction ,Nucleus - Abstract
Synthese du butyl-3 methyl-4 dioxa-2,6bicyclo [3.1.1] heptane par cyclodeshydratation du butyl-6 dibromo-3,3 methyl-5 perhydro pyrannediol-2,4(A) suivie de reduction par SnBu 3 H(A) est prepare a partir de methyl-2 heptene-2al
- Published
- 1985
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.