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27 results on '"Vazquez, Michael L."'

1. Macrocyclic Retinoic Acid Receptor-Related Orphan Receptor C2 Inverse Agonists

Author

Schnute, Mark E., primary, Trujillo, John I., additional, Lee, Katherine L., additional, Unwalla, Ray, additional, Vajdos, Felix F., additional, Kauppi, Björn, additional, Nuhant, Philippe, additional, Flick, Andrew C., additional, Crouse, Kimberly K., additional, Zhao, Yajuan, additional, Samuel, Amanda, additional, Lombardo, Vincent, additional, Taylor, Alexandria P., additional, Brault, Amy L., additional, Knafels, John D., additional, Vazquez, Michael L., additional, and Berstein, Gabriel, additional

Published
2023
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4. Evaluation of a Janus kinase 1 inhibitor, PF‐04965842, in healthy subjects: A phase 1, randomized, placebo‐controlled, dose‐escalation study

Author

Peeva, Elena, Hodge, Martin R., Kieras, Elizabeth, Vazquez, Michael L., Goteti, Kosalaram, Tarabar, Sanela G., Alvey, Christine W., and Banfield, Christopher

Subjects
Adult, Diarrhea, Male, Sulfonamides, Dose-Response Relationship, Drug, Headache, Nausea, Original Articles, Janus Kinase 1, Middle Aged, Drug Administration Schedule, Young Adult, Pyrimidines, Double-Blind Method, Area Under Curve, Humans, Female, Protein Kinase Inhibitors
Abstract

AIMS: To determine the safety, tolerability, pharmacokinetics and pharmacodynamics of the Janus kinase 1‐selective inhibitor, PF‐04965842. METHODS: This was a phase 1, first‐in‐human, randomized, double‐blind, placebo‐controlled, combination single‐ and multiple‐dose escalation, parallel design study in healthy subjects (http://clinicaltrials.gov, NCT01835197). Subjects received a single dose of placebo or 3, 10, 30, 100, 200, 400 or 800 mg PF‐04965842 (single ascending dose phase) and placebo or 30 mg once daily (QD), 100 mg QD, 200 mg QD, 400 mg QD, 100 mg twice daily (BID) or 200 mg BID PF‐04965842 for 10 consecutive days (multiple ascending dose phase). The primary objective was to determine the safety and tolerability of PF‐04965842. RESULTS: Seventy‐nine subjects were randomized and received study treatments. There were no deaths or serious adverse events. The most frequent treatment‐emergent adverse events were headache (n = 13), diarrhoea (n = 11) and nausea (n = 11). PF‐04965842 was absorbed rapidly (median time at which maximum plasma concentration occurred generally ≤1 h following either single‐ or multiple‐dose administration) and eliminated rapidly (mean t (½) 2.8−5.2 h after 10 days of QD or BID administration in the multiple ascending dose phase). Increases in maximum plasma concentration and area under the concentration–time curve were dose proportional up to 200 mg (single or total daily doses) with an apparent trend towards greater than proportional increases with higher doses. Less than 4.4% of the dose was recovered unchanged in urine. Changes in pharmacodynamic biomarkers were consistent with the known effects of Janus kinase signalling inhibition. CONCLUSIONS: These results support further evaluation of PF‐04965842 for clinical use in patients with inflammatory diseases.

Published
2018

5. Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases

Author

Vazquez, Michael L., Kaila, Neelu, Strohbach, Joseph W., Trzupek, John D., Brown, Matthew F., Flanagan, Mark E., Mitton-Fry, Mark J., Johnson, Timothy A., TenBrink, Ruth E., Arnold, Eric P., Basak, Arindrajit, Heasley, Steven E., Kwon, Soojin, Langille, Jonathan, Parikh, Mihir D., Griffin, Sarah H., Casavant, Jeffrey M., Duclos, Brian A., Fenwick, Ashley E., Harris, Thomas M., Han, Seungil, Caspers, Nicole, Dowty, Martin E., Yang, Xin, Banker, Mary Ellen, Hegen, Martin, Symanowicz, Peter T., Li, Li, Wang, Lu, Lin, Tsung H., Jussif, Jason, Clark, James D., Telliez, Jean-Baptiste, Robinson, Ralph P., and Unwalla, Ray

Abstract

Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation, and hematopoiesis. As JAK1 pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function while avoiding inhibition of the JAK2 homodimer regulating erythropoietin and thrombopoietin signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis. Through modification of the 3-aminopiperidine linker in tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar potency in a human whole blood assay. Improvements in JAK1 potency and selectivity were achieved via structural modifications suggested by X-ray crystallographic analysis. After demonstrating efficacy in a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (25) was nominated as a clinical candidate for the treatment of JAK1-mediated autoimmune diseases.

Published
2024
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7. Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases

Author

Vazquez, Michael L., primary, Kaila, Neelu, additional, Strohbach, Joseph W., additional, Trzupek, John D., additional, Brown, Matthew F., additional, Flanagan, Mark E., additional, Mitton-Fry, Mark J., additional, Johnson, Timothy A., additional, TenBrink, Ruth E., additional, Arnold, Eric P., additional, Basak, Arindrajit, additional, Heasley, Steven E., additional, Kwon, Soojin, additional, Langille, Jonathan, additional, Parikh, Mihir D., additional, Griffin, Sarah H., additional, Casavant, Jeffrey M., additional, Duclos, Brian A., additional, Fenwick, Ashley E., additional, Harris, Thomas M., additional, Han, Seungil, additional, Caspers, Nicole, additional, Dowty, Martin E., additional, Yang, Xin, additional, Banker, Mary Ellen, additional, Hegen, Martin, additional, Symanowicz, Peter T., additional, Li, Li, additional, Wang, Lu, additional, Lin, Tsung H., additional, Jussif, Jason, additional, Clark, James D., additional, Telliez, Jean-Baptiste, additional, Robinson, Ralph P., additional, and Unwalla, Ray, additional

Published
2018
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8. Development of a high-throughput crystal structure-determination platform for JAK1 using a novel metal-chelator soaking system

Author

Caspers, Nicole L., primary, Han, Seungil, additional, Rajamohan, Francis, additional, Hoth, Lise R., additional, Geoghegan, Kieran F., additional, Subashi, Timothy A., additional, Vazquez, Michael L., additional, Kaila, Neelu, additional, Cronin, Ciarán N., additional, Johnson, Eric, additional, and Kurumbail, Ravi G., additional

Published
2016
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9. Synthesis and biological evaluation of substituted benzoxazoles as inhibitors of mPGES-1: Use of a conformation-based hypothesis to facilitate compound design

Author

Walker, Daniel P., Arhancet, Graciela B., Lu, Hwang-Fun, Heasley, Steven E., Metz, Sue, Kablaoui, Natasha M., Franco, Francisco M., Hanau, Cathleen E., Scholten, Jeffrey A., Springer, John R., Fobian, Yvette M., Carter, Jeffrey S., Xing, Li, Yang, Shengtian, Shaffer, Alexander F., Jerome, Gina M., Baratta, Michael T., Moore, William M., and Vazquez, Michael L.

Published
2013
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12. Characterization of 3-carboxy-5-phosphono-1,2,3,4-tetrahydroisoquinoline (SC-48981), a potent competitive (NMDA) receptor antagonist, in vitro and in vivo

Author

Joseph B. Monahan, Eric T. Sun, S. Iyengar, Vazquez Michael L, Tadimeti S. Rao, S.J. Mick, Julie A. Cler, Danny J. Garland, and William F. Hood

Subjects
General Neuroscience, Antagonist, Glutamate receptor, Glycine receptor agonist, Pharmacology, Biology, Biochemistry, In vivo, Glycine, medicine, NMDA receptor, Receptor, Phencyclidine, medicine.drug
Abstract

(±)-3-Carboxy-5-phosphono-1,2,3,4-tetrahydroisoquinoline (SC-48981), a conformationally restricted analog of the potent competitive N-methyl-d-aspartate (NMDA) antagonist, 2-amino-5-phosphonopentanoate (AP-5), potently inhibited the binding of [3H]glutamate to the N-methyl-d-aspartate (NMDA) receptors with a Ki of 1.6 mcM, but with minimal affinity for kaininate and quisqualate receptors (Ki > 50 mcM), in vitro. Consistent with its ability to antagonize the NMDA receptor, SC-48981 decreased the binding of [3H]glycine and [3H]TCP [1-(2-thienyl)cyclohexylpiperidine] to the NMDA-associated glycine and phencyclidine (PCP) recognition sites, in vitro. SC-48981 attenuated levels of basal cGMP and harmaline-induced increases in levels of cGMP in the mouse cerebellum, in vivo, in a competitive manner, with ED50 values of 5.5 and 8.7 mg/kg, i.p. Direct intracerebellar injection of SC-48981 (0.5 μg) attenuated increases in levels of cGMP induced by central injection of the NMDA-associated glycine receptor agonist, D-serine and by NMDA itself. Parenteral administration of SC-48981 (25 mg/kg, s.c.) decreased basal levels of cGMP for up to 3 h. These results indicate that SC-48981 represents a novel bioavailable competitive NMDA antagonist with a long duration of action.

Published
1992

13. Benzodipyrazoles: a new class of potent CDK2 inhibitors

Author

Paolo Polucci, Suzanne Metz, Anna Vulpetti, Antonella Ermoli, M. Gabriella Brasca, Roberto D'Alessio, Alberto Bargiotti, Marcellino Tibolla, Alexander D. Cameron, Paolo Pevarello, Vazquez Michael L, Aurelio Marsiglio, and Fulvia Roletto

Subjects
Models, Molecular, medicine.drug_class, Clinical Biochemistry, Pharmaceutical Science, Carboxamide, Cyclin A, Crystallography, X-Ray, Biochemistry, Chemical synthesis, chemistry.chemical_compound, Glycogen Synthase Kinase 3, Structure-Activity Relationship, Cell Line, Tumor, Drug Discovery, medicine, CDC2-CDC28 Kinases, Humans, Enzyme Inhibitors, Cytotoxicity, Molecular Biology, Cell Proliferation, Hydroxamic acid, biology, Molecular Structure, Organic Chemistry, Cyclin-Dependent Kinase 2, Assay, chemistry, Cell culture, Enzyme inhibitor, biology.protein, Molecular Medicine, Pyrazoles, Signal transduction, Crystallization
Abstract

The synthesis and the preliminary expansion of this new class of CDK2 inhibitors are presented. The synthesis was accomplished using a solution-phase protocol amenable to rapid parallel expansion and suitable to be scaled-up in view of possible lead development. Following a medicinal chemistry program aimed at improving cell permeability and selectivity, a series of compounds with nanomolar activity in the biochemical assay and able to efficiently inhibit tumor cell proliferation has been obtained.

Published
2004

14. Renal effects induced by prolonged mPGES1 inhibition

Author

Salazar, Francisco, primary, Vazquez, Michael L., additional, Masferrer, Jaime L., additional, Mbalaviele, Gabriel, additional, Llinas, Maria T., additional, Saez, Fara, additional, Arhancet, Grace, additional, and Salazar, F. Javier, additional

Published
2014
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15. Homo-timeric structural model of human microsomal prostaglandin E synthase-1 and characterization of its substrate/inhibitor binding interactions

Author

Xing, Li, primary, Kurumbail, Ravi G., additional, Frazier, Ronald B., additional, Davies, Michael S., additional, Fujiwara, Hideji, additional, Weinberg, Robin A., additional, Gierse, James K., additional, Caspers, Nicole, additional, Carter, Jeffrey S., additional, McDonald, Joseph J., additional, Moore, William M., additional, and Vazquez, Michael L., additional

Published
2008
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16. Synthesis, Crystal Structure, and Activity of Pyrazole-Based Inhibitors of p38 Kinase

Author

Graneto, Matthew J., primary, Kurumbail, Ravi G., additional, Vazquez, Michael L., additional, Shieh, Huey-Sheng, additional, Pawlitz, Jennifer L., additional, Williams, Jennifer M., additional, Stallings, William C., additional, Geng, Lifeng, additional, Naraian, Ashok S., additional, Koszyk, Francis J., additional, Stealey, Michael A., additional, Xu, Xiangdong D., additional, Weier, Richard M., additional, Hanson, Gunnar J., additional, Mourey, Robert J., additional, Compton, Robert P., additional, Mnich, Stephen J., additional, Anderson, Gary D., additional, Monahan, Joseph B., additional, and Devraj, Rajesh, additional

Published
2007
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17. A review of the in vitro and in vivo neurochemical characterization of the NMDA/PCP/glycine/ion channel receptor macrocomplex

Author

Tadimeti S. Rao, Vazquez Michael L, Paul L. Wood, Patricia C. Contreras, Nancy M. Gray, S. Iyengar, Thomas H. Lanthorn, Alex Cordi, Joseph B. Monahan, and Eric T. Sun

Subjects
Receptor complex, Brain, Neural degeneration, General Medicine, Biology, Biochemistry, Receptors, N-Methyl-D-Aspartate, In vitro, Receptors, Neurotransmitter, Cellular and Molecular Neuroscience, Neurochemical, Receptors, Glycine, NMDA receptor, Animals, Humans, Receptors, Phencyclidine, Receptor, Glycine receptor, Neuroscience, Ion channel
Abstract

Current neurochemical studies of the NMDA receptor macromolecular complex are yielding new insights into the interactions of the subunits of this complex and the associated potential clinical benefits of selective modulation of these subnits. Such studies offer the great potential for a new generation of pharmacotherapies for a wide range of CNS disorders, including stroke, a condition for which there is currently no effective pharmacological treatment. However, it is essential to understand that the first generation products in this area may not be optimal pharmacotherapies, such that haracterization of possible receptor subtypes and understanding the molecular biology of the component proteins of the receptor complex will be crucial in the design of the optimal pharmacological modulators of the NMDA receptor complex.

Published
1990

18. Benzodipyrazoles: a new class of potent CDK2 inhibitors

Author

D’Alessio, Roberto, primary, Bargiotti, Alberto, additional, Metz, Suzanne, additional, Brasca, M. Gabriella, additional, Cameron, Alexander, additional, Ermoli, Antonella, additional, Marsiglio, Aurelio, additional, Polucci, Paolo, additional, Roletto, Fulvia, additional, Tibolla, Marcellino, additional, Vazquez, Michael L., additional, Vulpetti, Anna, additional, and Pevarello, Paolo, additional

Published
2005
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19. Renal effects induced by prolonged mPGES1 inhibition.

Author

Salazar, Francisco, Vazquez, Michael L., Masferrer, Jaime L., Mbalaviele, Gabriel, Llinas, Maria T., Saez, Fara, Arhancet, Grace, and Javier Salazar, F.

Subjects
*EXCRETORY organs, *HEMODYNAMICS, *PROSTAGLANDIN antagonists, *SODIUM, *ASPARTIC proteinases, *THERAPEUTICS, RENAL artery diseases
Abstract

Renal effects induced by prolonged mPGES1 inhibition. Am J Physiol Renal Physiol 306: F68-F74, 2014. First published November 6, 2013; doi:10.1152/ajprenal.00492.2013.-The importance of membrane-bound PGE synthase 1 (mPGES1) in the regulation of renal function has been examined in mPGES1-deficient mice or by evaluating changes in its expression. However, it is unknown whether prolonged mPGES1 inhibition induces significant changes of renal function when Na+ intake is normal or low. This study examined the renal effects elicited by a selective mPGES1 inhibitor (PF-458) during 7 days in conscious chronically instrumented dogs with normal Na+ intake (NSI) or low Na+ intake (LSI). Results obtained in both in vitro and in vivo studies have strongly suggested that PF-458 is a selective mPGES1 inhibitor. The administration of 2.4 mg.kg-1.day-1 PF-458 to dogs with LSI did not induce significant changes in renal blood flow (RBF) and glomerular filtration rate (GFR). A larger dose of PF-458 (9.6 mg.kg-1.day-1) reduced RBF (P < 0.05) but not GFR in dogs with LSI and did not induce changes of renal hemodynamic in dogs with NSI. Both doses of PF-458 elicited a decrease (P < 0.05) in PGE2 and an increase (P < 0.05) in 6-keto-PGF1α. The dministration of PF-458 did not induce significant changes in renal excretory function, plasma renin activity, and plasma aldosterone and thromboxane B2 concentrations in dogs with LSI or NSI. The results obtained suggest that mPGES1 is involved in the regulation of RBF when Na+ intake is low and that the renal effects elicited by mPGES1 inhibition are modulated by a compensatory increment in PGI2. These results may have some therapeutical implications since it has been shown that prolonged mPGES1 inhibition has lower renal effects than those elicited by nonsteroidal anti-inflammatory drugs or selective cyclooxygenase-2 inhibitors. [ABSTRACT FROM AUTHOR]

Published
2014
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21. Inhibitors of HIV-1 Protease Containing the Novel and Potent (R)-(Hydroxyethyl)sulfonamide Isostere

Author

Vazquez, Michael L., primary, Bryant, Martin L., additional, Clare, Michael, additional, DeCrescenzo, Gary A., additional, Doherty, Elizabeth M., additional, Freskos, John N., additional, Getman, Daniel P., additional, Houseman, Kathryn A., additional, Julien, Janet A., additional, Kocan, Geralyn P., additional, Mueller, Richard A., additional, Shieh, Huey-Sheng, additional, Stallings, William C., additional, Stegeman, Roderick A., additional, and Tilley, John J., additional

Published
1995
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23. A Practical Synthesis of [(1S,3S)-3-Aminocyclohexyl]methanol and 2-[(1S,3S)-3-Aminocyclohexyl]propan-2-ol, Useful Intermediates for the Preparation of Novel mPGES-1 Inhibitors.

Author

Walker, Daniel P., Heasley, Steven E., MacInnes, Allison, Anjeh, Tizah, Hwang-Fun Lu, Fobian, Yvette M., Collins, Joe T., Vazquez, Michael L., and Mao, Michael K.

Subjects
CHEMICAL synthesis, METHANOL, AMINO alcohols, CARBOCYCLIC acids, CHIRALITY, ANTI-inflammatory agents
Abstract

Microsomal prostaglandin E2 synthase-1 (mPGES-1) is a novel therapeutic target for the treatment of inflammation and pain. During the course of studies aimed at the identification of a suitable mPGES-1 inhibitor for clinical development, a need arose for preparing enantiomerically enriched amino alcohols (S,S)-2 and (S,S)-3. Described herein, a concise synthesis of (S,S)-2 and (S,S)-3 has been developed wherein both amino alcohols are derived from a commercially available, low-cost starting material. [ABSTRACT FROM AUTHOR]

Published
2011
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24. Homo-timeric structural model of human microsomal prostaglandin E synthase-1 and characterization of its substrate/inhibitor binding interactions.

Author

Li Xing, Kurumbail, Ravi G., Frazier, Ronald B., Davies, Michael S., Fujiwara, Hideji, Weinberg, Robin A., Gierse, James K., Caspers, Nicole, Carter, Jeffrey S., McDonald, Joseph J., Moore, William M., and Vazquez, Michael L.

Subjects
PROSTAGLANDIN E1, GLUCAN synthase, ENZYME regulation, BIOCHEMISTRY, MONOMERS
Abstract

Inducible, microsomal prostaglandin E synthase 1 (mPGES-1), the terminal enzyme in the prostaglandin (PG) biosynthetic pathway, constitutes a promising therapeutic target for the development of new anti-inflammatory drugs. To elucidate structure–function relationships and to enable structure-based design, an mPGES-1 homology model was developed using the three-dimensional structure of the closest homologue of the MAPEG family (Membrane Associated Proteins in Eicosanoid and Glutathione metabolism), mGST-1. The ensuing model of mPGES-1 is a homo-trimer, with each monomer consisting of four membrane-spanning segments. Extensive structure refinement revealed an inter-monomer salt bridge (K26-E77) as well as inter-helical interactions within each monomer, including polar hydrogen bonds (e.g. T78-R110-T129) and hydrophobic π-stacking (F82-F103-F106), all contributing to the overall stability of the homo-trimer of mPGES-1. Catalytic co-factor glutathione (GSH) was docked into the mPGES-1 model by flexible optimization of both the ligand and the protein conformations, starting from the initial location ascertained from the mGST-1 structure. Possible binding site for the substrate, prostaglandin H2 (PGH2), was identified by systematically probing the refined molecular structure of mPGES-1. A binding model was generated by induced fit docking of PGH2 in the presence of GSH. The homology model prescribes three potential inhibitor binding sites per mPGES-1 trimer. This was further confirmed experimentally by equilibrium dialysis study which generated a binding stoichiometric ratio of approximately three inhibitor molecules to three mPGES-1 monomers. The structural model that we have derived could serve as a useful tool for structure-guided design of inhibitors for this emergently important therapeutic target. [ABSTRACT FROM AUTHOR]

Published
2009
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25. Binding of the hydroxyethyl-urea isostere to HIV-1 protease

Author

John J. Talley, Roderick A. Stegeman, Kathryn Houseman, Heintz Robert M, Decrescenzo Gary A, Daniel P. Getman, Richard A. Mueller, Vazquez Michael L, K.L. Reed, M.E. Gustafson, Michael Clare, Huey-Sheng Shieh, William C. Stallings, and K.D. Junger

Subjects
HIV-1 protease, biology, Structural Biology, Stereochemistry, Isostere, Chemistry, biology.protein, Hydroxyethyl Urea
Published
1993

27. Benzodipyrazoles: a new class of potent CDK2 inhibitors.

Author

D'Alessio R, Bargiotti A, Metz S, Brasca MG, Cameron A, Ermoli A, Marsiglio A, Polucci P, Roletto F, Tibolla M, Vazquez ML, Vulpetti A, and Pevarello P

Subjects
Cell Line, Tumor, Cell Proliferation drug effects, Crystallization, Crystallography, X-Ray, Cyclin A antagonists & inhibitors, Cyclin-Dependent Kinase 2, Enzyme Inhibitors chemical synthesis, Glycogen Synthase Kinase 3 antagonists & inhibitors, Humans, Models, Molecular, Molecular Structure, Pyrazoles chemical synthesis, Structure-Activity Relationship, CDC2-CDC28 Kinases antagonists & inhibitors, Enzyme Inhibitors classification, Enzyme Inhibitors pharmacology, Pyrazoles classification, Pyrazoles pharmacology
Abstract

The synthesis and the preliminary expansion of this new class of CDK2 inhibitors are presented. The synthesis was accomplished using a solution-phase protocol amenable to rapid parallel expansion and suitable to be scaled-up in view of possible lead development. Following a medicinal chemistry program aimed at improving cell permeability and selectivity, a series of compounds with nanomolar activity in the biochemical assay and able to efficiently inhibit tumor cell proliferation has been obtained.

Published
2005
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