119 results on '"Yong-Jin Wu"'
Search Results
2. Baloxavir Marboxil (Xofluza), A Cap‐Dependent Endonuclease Inhibitor for Treating Influenza
- Author
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Yong‐Jin Wu
- Published
- 2022
3. 5-Bromo-2-chloro-4-fluoro-3-iodopyridine as a Halogen-rich Intermediate for the Synthesis of Pentasubstituted Pyridines
- Author
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Yong-Jin Wu, Gerard J. Porter, David B. Frennesson, and Mark G. Saulnier
- Subjects
Halogens ,Pyridines ,Organic Chemistry ,Chlorine ,Bromine ,Iodine - Abstract
The 60 individual halopyridine isomers that contain one bromine, chlorine, fluorine, iodine, and H are valuable potential building blocks in medicinal chemistry research, but surprisingly, there has been only one report on the synthesis of just two of them. Herein, we describe simple syntheses of the unique 5-bromo-2-chloro-4-fluoro-3-iodopyridine (
- Published
- 2022
4. Geminal Diheteroatomic Motifs: Some Applications of Acetals, Ketals, and Their Sulfur and Nitrogen Homologues in Medicinal Chemistry and Drug Design
- Author
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Yong-Jin Wu and Nicholas A. Meanwell
- Subjects
Drug ,Molecular Structure ,Geminal ,Nitrogen ,Chemistry ,Chemistry, Pharmaceutical ,media_common.quotation_subject ,Design elements and principles ,chemistry.chemical_element ,Ketones ,Combinatorial chemistry ,Sulfur ,Acetals ,Drug Design ,Drug Discovery ,Molecular Medicine ,Molecule ,Upper gastrointestinal ,Chemical stability ,Pharmacophore ,media_common - Abstract
Acetals and ketals and their nitrogen and sulfur homologues are often considered to be unconventional and potentially problematic scaffolding elements or pharmacophores for the design of orally bioavailable drugs. This opinion is largely a function of the perception that such motifs might be chemically unstable under the acidic conditions of the stomach and upper gastrointestinal tract. However, even simple acetals and ketals, including acyclic molecules, can be sufficiently robust under acidic conditions to be fashioned into orally bioavailable drugs, and these structural elements are embedded in many effective therapeutic agents. The chemical stability of molecules incorporating geminal diheteroatomic motifs can be modulated by physicochemical design principles that include the judicious deployment of proximal electron-withdrawing substituents and conformational restriction. In this Perspective, we exemplify geminal diheteroatomic motifs that have been utilized in the discovery of orally bioavailable drugs or drug candidates against the backdrop of understanding their potential for chemical lability.
- Published
- 2021
5. A Multi-Inlet Microfluidic Nozzle Head with Shape Memory Alloy-Based Switching for Biomaterial Printing with Precise Flow Control
- Author
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Chia Yuan Chen, Karthick Mani, Bivas Panigrahi, Yong Jin Wu, Wei Chen Lin, Chun Fang Wang, and Cheng Lung Wu
- Subjects
Scaffold ,3D bioprinting ,Computer science ,010401 analytical chemistry ,Microfluidics ,Biomedical Engineering ,Biomaterial ,Mechanical engineering ,Bioengineering ,02 engineering and technology ,021001 nanoscience & nanotechnology ,SMA ,01 natural sciences ,0104 chemical sciences ,law.invention ,Flow control (fluid) ,law ,Proof of concept ,Electrical and Electronic Engineering ,0210 nano-technology ,Actuator ,Biotechnology - Abstract
3D bioprinting is one of the rapidly evolving fields of tissue engineering where microengineering meets cells biology within an unprecedented precision to construct tissue structures of various forms with complexity. However, enabling simultaneous printing of heterogeneous biomaterial along with scaffold components through the currently available printers is still considered as a major challenge due to the lack of instrumentation. Flow control is one of the major issues associated with the process. In this aspect, a microfluidic nozzle head equipped with two shape-memory alloy (SMA) actuators was proposed and integrated with a commercially available 3D printer to assist the biomaterial printing in a more systematic manner. The SMA actuator restrains the amount of flows for fabricating the desired scaffold components. Experimental results illustrated that the use of SMA actuator ensued a rapid and precise flow control of biomaterial and can further facilitate to maintain the width of any printed structures. As a proof of concept for the profound biomedical applications with the present manufacturing configuration, a 3D printed hydrogel platform was fabricated with demonstrated characters for later cell seeding after the printing further opens a new chapter in terms of biomaterial printing.
- Published
- 2020
6. Soluble CD83 alleviates experimental allergic rhinitis through modulating antigen-specific Th2 cell property
- Author
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Da-Bo Liu, Li-Hua Mo, Xiao-Rui Geng, Zhigang Liu, Xiaowen Zhang, Fei Ma, Yan-Nan Song, Yong-Jin Wu, and Ping-Chang Yang
- Subjects
Adult ,CD4-Positive T-Lymphocytes ,Male ,Allergy ,nasal mucosa ,T cell ,Cell ,Blotting, Western ,Immunoglobulins ,Muscle Proteins ,Mucous membrane of nose ,Enzyme-Linked Immunosorbent Assay ,Applied Microbiology and Biotechnology ,Pathogenesis ,03 medical and health sciences ,CD4+ T cell ,Mice ,Immune system ,Th2 Cells ,CD83 ,Antigens, CD ,medicine ,Hypersensitivity ,Animals ,Humans ,Immunoprecipitation ,Inducer ,Clustered Regularly Interspaced Short Palindromic Repeats ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,0303 health sciences ,Membrane Glycoproteins ,Chemistry ,immune regulation ,Pyroglyphidae ,Cell Biology ,medicine.disease ,Rhinitis, Allergic ,medicine.anatomical_structure ,Proto-Oncogene Proteins c-bcl-2 ,Apoptosis ,Immunology ,Female ,RNA Interference ,Developmental Biology ,Research Paper - Abstract
Background and aims: Dysfunction of the immune regulatory system plays a role in the pathogenesis of allergic rhinitis (AR). The underlying mechanism needs to be further investigated. Published data indicate that soluble CD83 (sCD83) has immune regulatory activities. This study aims to investigate the role of sCD83 in the alleviation of experimental AR. Methods: Peripheral blood samples were obtained from AR patients. Serum levels of sCD83 were determined by enzyme-linked immunosorbent assay. A murine AR model was developed to test the effects of sCD83 on suppressing experimental AR. Results: We found that serum levels of sCD83 in the AR group were lower than that in the healthy control group. A negative correlation was identified between the serum sCD83 levels and the frequency of T helper-2 (Th2) cells. The low serum sCD83 levels were also associated with the Bcl2L12 expression in antigen-specific Th2 cells. Exposure to sCD83 enhanced the responsiveness of antigen-specific Th2 cells to apoptosis inducers via suppressing the Bcl2L12 expression. Administration of sCD83 efficiently suppressed experimental AR. Conclusions: sCD83 contributes to immune homeostasis by regulating CD4+ T cell activities. Administration of sCD83 may have translational potential for the treatment of AR or other allergic diseases.
- Published
- 2020
7. The Effect Mechanism and Model Optimization of Pulsed Light Dark Duration on Lettuce
- Author
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Yong-jin Wu, Sun-tao Mou, Yi Liu, Huibin Yu, guan-zhi zhang, Xiaodong Xu, Zhenchao Yang, Yahui Bai, and Li-yuan Ma
- Subjects
Chemistry ,Duration (music) ,Biophysics ,Mechanism (sociology) - Abstract
Background: Despite its rapid development, the costs of crop artificial light source technology are still high. In addition, both the luminous efficiency and photosynthetic light supplement efficiency of the light source require further improvement. This study aims to improve the photosynthetic light supplement efficiency by altering the luminescence mode of the light source, transforming the conventional continuous supplementary light source into a pulse light source, and exploring how to further reduce energy consumption and improve the light supplement efficiency without influencing the light supplement effect of Lettuce.Results: For this purpose, Lettuce (Lactuca sativa L.) was selected as the experimental material to investigate the effects of varying the duty ratio, frequency and dark duration on the Pn (net photosynthetic rate) of leaves. The results revealed that Pn values under each duty ratio treatment increased with frequency and gradually stabilized to a level similar to that of continuous light. At higher duty ratios, the lettuce leaf Pn under pulse light reached a stable state at a lower frequency, with Pn leveling showing an overall upward trend with the decreasing dark period duration and a large increase in the early stage. For dark period durations lower than a certain value (0.000683594 s), variations in Pn among treatments were minimal, with a gradual increasing trend until no significant differences are observed with continuous light (CK); Under the D3 (weak light) condition, plants were easy to spindling(excessive growth)and exhibited narrow and slender leaves. Plants under the D2 condition (The duration period duration was 0.000465468s) presented the strongest roots and stems, with wide leaves and a compact growth. The following trend in Pn was observed across all duty ratios D2>D1 (0.000046547s)>CK>D3 (0.004654685s). Conclusions: The dominant influencing factor of the plant net photosynthetic rate was determined as the ratio of the frequency and duty ratio (i.e., dark period duration). Compared with continuous light, pulsed light is more beneficial to plant growth and utilization.
- Published
- 2021
8. Discovery of new indole-based acylsulfonamide Nav1.7 inhibitors
- Author
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Carolyn Diane Dzierba, Linda J. Bristow, Ramkumar Rajamani, Jie Chen, Rick L. Pieschl, Sing-Yuen Sit, Brian Lee Venables, Michele Matchett, Ronald J. Knox, Lorin A. Thompson, Nicholas A. Meanwell, Yong-Jin Wu, Jason M. Guernon, and James Herrington
- Subjects
Indole test ,Gene isoform ,Membrane permeability ,010405 organic chemistry ,Chemistry ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Ring (chemistry) ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Drug Discovery ,Molecular Medicine ,Potency ,Moiety ,Efflux ,Selectivity ,Molecular Biology - Abstract
Screening of 100 acylsulfonamides from the Bristol-Myers Squibb compound collection identified the C3-cyclohexyl indole 6 as a potent Nav1.7 inhibitor. Replacement of the C2 furanyl ring of 6 with a heteroaryl moiety or truncation of this group led to the identification of 4 analogs with hNav1.7 IC50 values under 50 nM. Fluorine substitution of the truncated compound 12 led to 34 with improved potency and isoform selectivity. The inverted indole 36 also maintained good activity. Both 34 and 36 exhibited favorable CYP inhibition profiles, good membrane permeability and a low efflux ratio and, therefore, represent new leads in the search for potent and selective Nav1.7 inhibitors to treat pain.
- Published
- 2019
9. Identification and Preclinical Evaluation of the Bicyclic Pyrimidine γ-Secretase Modulator BMS-932481
- Author
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John E. Macor, Yunhui Zhang, James E. Grace, Lorin A. Thompson, Jeremy H. Toyn, Lawrence R. Marcin, Subramaniam Krishnananthan, Jianliang Shi, Dmitry Zuev, Daniel Smith, Jianqing Li, Yong-Jin Wu, Jason M. Guernon, Xiaoliang Zhuo, Tatyana Zvyaga, Xu Li, Arvind Mathur, John Morrison, Jere E. Meredith, Charles F. Albright, S. Roy Kimura, Mendi A. Higgins, Kimberley A. Lentz, Richard E. Olson, Rex Denton, Kenneth M. Boy, Catherine R. Burton, Ashok K. Trehan, and Michael K. Ahlijanian
- Subjects
gamma-secretase modulator ,Letter ,Bicyclic molecule ,Pyrimidine ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,bicyclic pyrimidine ,clinical candidate ,γ secretase modulator ,Pharmacology ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,Cerebrospinal fluid ,In vivo ,Drug Discovery ,Toxicity ,Potency ,Alzheimer’s disease ,Triazine - Abstract
A triazine hit identified from a screen of the BMS compound collection was optimized for potency, in vivo activity, and off-target profile to produce the bicyclic pyrimidine γ-secretase modulator BMS-932481. The compound showed robust reductions of Aβ1–42 and Aβ1–40 in the plasma, brain, and cerebrospinal fluid of mice and rats. Consistent with the γ-secretase modulator mechanism, increases in Aβ1–37 and Aβ1–38 were observed, with no change in the total amount of Aβ1–x produced. No Notch-based toxicity was observed, and the overall preclinical profile of BMS-932481 supported its further evaluation in human clinical trials.
- Published
- 2019
10. SNAr reactions of 5-bromo-2-chloro-4-fluoro-3-iodopyridine and its 3-substituted analogs
- Author
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Gerard Porter, Mark Saulnier, and Yong-Jin Wu
- Subjects
Organic Chemistry ,Drug Discovery ,Biochemistry - Published
- 2022
11. B cell lymphoma-2-like protein-12 association with T-helper 2 inflammation in chronic rhinosinusitis with allergy
- Author
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Yong-Jin Wu, Yun-Fang An, Chang-Qing Zhao, Xian-Hai Zeng, Lijuan Song, Liao Wenjing, Zhi-Qiang Liu, Ping-Chang Yang, Fei Ma, Gui Yang, Zhigang Liu, and Xiaowen Zhang
- Subjects
0301 basic medicine ,Allergy ,biology ,business.industry ,Lymphocyte ,Mucous membrane of nose ,Immune dysregulation ,Immunoglobulin E ,medicine.disease_cause ,medicine.disease ,Pathogenesis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,030228 respiratory system ,Otorhinolaryngology ,Immunology ,otorhinolaryngologic diseases ,medicine ,biology.protein ,Immunology and Allergy ,business ,B cell ,Interleukin 4 - Abstract
Background T-helper 2 (Th2) polarization plays a critical role in the pathogenesis of chronic rhinosinusitis (CRS) with accompanying nasal allergy. Recent studies indicate that B cell lymphoma-2-like protein-12 (Bcl2L12) is associated with immune dysregulation. The purpose of this study was to elucidate the role of Bcl2L12 in the pathogenesis of Th2 polarization of CRS patients. Methods CRS patients with nasal allergy (CRSa) and without nasal allergy (CRSna) were recruited into this study. CD4+ T cells were isolated from the blood samples of human subjects. A variety of immunologic molecular strategies were used to assess Th2 polarization and Bcl2L12 expression. Results Twenty CRSa patients, 20 CRSna patients, and 20 healthy subjects were recruited into this study. High levels of immunoglobulin E (IgE), interleukin 4 (IL-4), IL-5, IL-13, and Bcl2L12 were detected in nasal extracts of CRSa patients, but not in CRSna patients. The levels of Bcl2L12 were positively correlated with Th2 cytokines. CD4+ T cells from CRSa patients were prone to differentiate into Th2 cells, in which Bcl2L12 was required. Conclusion Bcl2L12 is positively correlated with Th2 cytokine levels in the nasal mucosa of CRSa patients. Bcl2L12 contributes to the Th2 polarization, which may be a novel therapeutic target in the treatment of CRSa.
- Published
- 2018
12. Five-membered ring systems: with N and S atoms
- Author
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Yong-Jin Wu
- Published
- 2021
13. Molecules Engineered Against Oncogenic Proteins and Cancer : Discovery, Design, and Development
- Author
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E. J. Corey, Yong-Jin Wu, E. J. Corey, and Yong-Jin Wu
- Subjects
- Cancer--Treatment, Protein-tyrosine kinase--Inhibitors--Therapeutic use, Carcinogenesis--Molecular aspects
- Abstract
Molecules Engineered Against Oncogenic Proteins and Cancer A comprehensive review of the latest molecular advances in cancer treatment Featuring 91 total small molecule kinase/KRAS inhibitors, 80 of which are FDA-approved, Molecules Engineered Against Oncogenic Proteins and Cancer documents the recent scientific advances that have transformed one of medicine's most challenging areas—cancer treatment. Most of these inhibitors specifically block oncogene-induced carcinogenic proteins with results that have dramatically advanced the treatment of cancer. In addition, the structural formulas of more than 100 kinase/KRAS inhibitors in clinical trials are presented. With a very well-known chemist as an author, Molecules Engineered Against Oncogenic Proteins and Cancer includes information on: Each molecule's structure, function of the kinase target and relevance to cancer, the drug discovery process, and molecular details of drug action Mutated protein kinases as oncoproteins and targets for inhibition, along with the details of discovery for each antitumor antikinase agent History of oncoprotein inhibitors and their role in advancing the treatment and understanding of cancer The discovery process as a whole, effective strategies for innovation, ongoing challenges, and a glimpse of the future of the field Combining the most significant recent discoveries in a unique and useful way, Molecules Engineered Against Oncogenic Proteins and Cancer is an essential resource for researchers and students in bioscience, medicine, chemistry, and oncology as well as for those at industrial companies involved in therapeutic discovery.
- Published
- 2024
14. Histone deacetylase 11 inhibits interleukin 10 in B cells of subjects with allergic rhinitis
- Author
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Da-Bo Liu, Jian-Bo Shao, Mao-Gang Li, Zhigang Liu, Li-Hua Mo, Jing-Yi Hong, Xiang-Qian Luo, Huabin Li, Ping-Chang Yang, and Yong-Jin Wu
- Subjects
0301 basic medicine ,HDAC11 ,business.industry ,Interleukin ,Immune tolerance ,03 medical and health sciences ,Interleukin 10 ,030104 developmental biology ,Immune system ,medicine.anatomical_structure ,Otorhinolaryngology ,Cancer research ,Immunology and Allergy ,Medicine ,Tumor necrosis factor alpha ,Histone deacetylase ,business ,B cell - Abstract
Background The interleukin (IL)-10 expression in B cells plays an important role in immune tolerance. The regulation of IL-10 expression in B cells is not fully understood yet. Tumor necrosis factor (TNF) is increased in allergic rhinitis (AR) patients. This study tests a hypothesis that TNF enhances histone deacetylase (HDAC)11 expression to inhibit the expression of IL-10 in B cells of AR patients. Methods Peripheral B cells were collected from healthy persons and patients with AR. The B cells were analyzed by immune assay and molecular biological approaches for the expression of IL-10. Results The expression of HDAC11 was higher in B cells of patients with AR than that in healthy persons. The expression of IL-10 in B cells was lower in AR patients than that in healthy subjects. The levels of HDAC11 in B cells were negatively correlated with the levels of IL-10. Exposure of B cells to TNF in the culture inhibited the expression of IL-10, in which HDAC11 played a critical role in the interference with the Il10 gene transcription. Inhibition of HDAC11 restored the IL-10 expression in B cells from AR patients and attenuated the experimental AR. Conclusion TNF can suppress the expression of IL-10 in B cells via enhancing the expression of HDAC11. Inhibition of HDAC11 restores the IL-10 expression in B cells of AR subjects. HDAC11 may be a novel target for the treatment of AR.
- Published
- 2018
15. Discovery of morpholine-based aryl sulfonamides as Na v 1.7 inhibitors
- Author
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Nicholas A. Meanwell, Kevin J. Robbins, Carolyn Diane Dzierba, Rick L. Pieschl, Ramkumar Rajamani, James Herrington, Lorin A. Thompson, Andrea McClure, Yong-Jin Wu, Michele Matchett, Ronald J. Knox, Brian Lee Venables, Jason M. Guernon, Linda J. Bristow, and Richard E. Olson
- Subjects
0301 basic medicine ,010405 organic chemistry ,Aryl ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Ring (chemistry) ,01 natural sciences ,Biochemistry ,Combinatorial chemistry ,0104 chemical sciences ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,chemistry ,Morpholine ,Drug Discovery ,Molecular Medicine ,Structure–activity relationship ,Piperidine ,Molecular Biology - Abstract
Replacement of the piperidine ring in the lead benzenesulfonamide Nav1.7 inhibitor 1 with a weakly basic morpholine core resulted in a significant reduction in Nav1.7 inhibitory activity, but the activity was restored by shortening the linkage from methyleneoxy to oxygen. These efforts led to a series of morpholine-based aryl sulfonamides as isoform-selective Nav1.7 inhibitors. This report describes the synthesis and SAR of these analogs.
- Published
- 2018
16. Discovery of non-zwitterionic aryl sulfonamides as Nav1.7 inhibitors with efficacy in preclinical behavioral models and translational measures of nociceptive neuron activation
- Author
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Kathleen W. Mosure, Michele Matchett, Ronald J. Knox, Richard E. Olson, Joanne J. Bronson, Nicholas A. Meanwell, Matthew G. Soars, Linda J. Bristow, Ramkumar Rajamani, James Herrington, Amy Easton, Digavalli V. Sivarao, Dawn D. Parker, Rick L. Pieschl, Ping Chen, Guanglin Luo, Omar S. Barnaby, Lorin A. Thompson, Yong-Jin Wu, Andrea McClure, Jason M. Guernon, Amy Newton, Alicia Ng, Clotilde Bourin, and Carolyn Diane Dzierba
- Subjects
0301 basic medicine ,chemistry.chemical_classification ,Membrane permeability ,Bicyclic molecule ,Aryl ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,Sulfonamide ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,medicine.anatomical_structure ,Nociception ,chemistry ,Drug Discovery ,NAV1 ,medicine ,Molecular Medicine ,Moiety ,Neuron ,Molecular Biology - Abstract
Since zwitterionic benzenesulfonamide Nav1.7 inhibitors suffer from poor membrane permeability, we sought to eliminate this characteristic by replacing the basic moiety with non-basic bicyclic acetals and monocyclic ethers. These efforts led to the discovery of the non-zwitterionic aryl sulfonamide 49 as a selective Nav1.7 inhibitor with improved membrane permeability. Despite its moderate cellular activity, 49 exhibited robust efficacy in mouse models of neuropathic and inflammatory pain and modulated translational electromyogram measures associated with activation of nociceptive neurons.
- Published
- 2017
17. Development of New Benzenesulfonamides As Potent and Selective Nav1.7 Inhibitors for the Treatment of Pain
- Author
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Debra J. Post-Munson, Amy Easton, Carolyn Diane Dzierba, Amy Newton, Yong-Jin Wu, Ronald J. Knox, Kevin J. Robbins, Jason M. Guernon, Clotilde Bourin, Ramkumar Rajamani, Richard E. Olson, James Herrington, Michele Matchett, Kimberly Newberry, John D. Graef, Jianliang Shi, Lorin A. Thompson, Shuya Wang, Jonathan L. Ditta, Nicholas A. Meanwell, Rick L. Pieschl, Matthew G. Soars, Linda J. Bristow, and Kathleen W. Mosure
- Subjects
0301 basic medicine ,Formalin Test ,Membrane permeability ,010405 organic chemistry ,Drug discovery ,Stereochemistry ,Cyclohexylamine ,Pharmacology ,01 natural sciences ,0104 chemical sciences ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Dorsal root ganglion ,Drug Discovery ,NAV1 ,medicine ,Molecular Medicine ,Piperidine - Abstract
By taking advantage of certain features in piperidine 4, we developed a novel series of cyclohexylamine- and piperidine-based benzenesulfonamides as potent and selective Nav1.7 inhibitors. However, compound 24, one of the early analogs, failed to reduce phase 2 flinching in the mouse formalin test even at a dose of 100 mpk PO due to insufficient dorsal root ganglion (DRG) exposure attributed to poor membrane permeability. Two analogs with improved membrane permeability showed much increased DRG concentrations at doses of 30 mpk PO, but, confoundingly, only one of these was effective in the formalin test. More data are needed to understand the disconnect between efficacy and exposure relationships.
- Published
- 2017
18. Discovery of new indole-based acylsulfonamide Na
- Author
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Yong-Jin, Wu, Brian, Venables, Jason, Guernon, Jie, Chen, Sing-Yuen, Sit, Ramkumar, Rajamani, Ronald J, Knox, Michele, Matchett, Rick L, Pieschl, James, Herrington, Linda J, Bristow, Nicholas A, Meanwell, Lorin A, Thompson, and Carolyn, Dzierba
- Subjects
Inhibitory Concentration 50 ,Structure-Activity Relationship ,Sulfonamides ,Indoles ,Drug Discovery ,NAV1.7 Voltage-Gated Sodium Channel ,Humans - Abstract
Screening of 100 acylsulfonamides from the Bristol-Myers Squibb compound collection identified the C3-cyclohexyl indole 6 as a potent Na
- Published
- 2018
19. The discovery of VU0652957 (VU2957, Valiglurax): SAR and DMPK challenges en route to an mGlu
- Author
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Joseph D, Panarese, Darren W, Engers, Yong-Jin, Wu, Jason M, Guernon, Aspen, Chun, Alison R, Gregro, Aaron M, Bender, Rory A, Capstick, Joshua M, Wieting, Joanne J, Bronson, John E, Macor, Ryan, Westphal, Matthew, Soars, Julie E, Engers, Andrew S, Felts, Alice L, Rodriguez, Kyle A, Emmitte, Carrie K, Jones, Anna L, Blobaum, P Jeffrey, Conn, Colleen M, Niswender, Corey R, Hopkins, and Craig W, Lindsley
- Subjects
Structure-Activity Relationship ,Allosteric Regulation ,Dose-Response Relationship, Drug ,Molecular Structure ,Drug Discovery ,Humans ,Isoquinolines ,Receptors, Metabotropic Glutamate ,Heterocyclic Compounds, 2-Ring ,Myotonin-Protein Kinase - Abstract
This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu
- Published
- 2018
20. Synthesis of functionalized derivatives of the gamma-secretase modulator BMS-932481 and identification of its major metabolite
- Author
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John E. Macor, Benjamin M. Johnson, Richard E. Olson, Rex Denton, Michael K. Ahlijanian, Charles F. Albright, Yong-Jin Wu, Antonio Ramirez, Jeremy H. Toyn, Lorin A. Thompson, Xiaoliang Zhuo, Yunhui Zhang, and Kenneth M. Boy
- Subjects
Pyrimidine ,Metabolite ,education ,Clinical Biochemistry ,Pharmaceutical Science ,Alcohol ,01 natural sciences ,Biochemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,In vivo ,Drug Discovery ,Animals ,Humans ,Molecular Biology ,Gamma secretase ,Aniline Compounds ,Dose-Response Relationship, Drug ,Molecular Structure ,Bicyclic molecule ,010405 organic chemistry ,digestive, oral, and skin physiology ,Organic Chemistry ,In vitro ,Rats ,0104 chemical sciences ,stomatognathic diseases ,010404 medicinal & biomolecular chemistry ,Pyrimidines ,chemistry ,Microsomes, Liver ,Microsome ,Molecular Medicine ,Amyloid Precursor Protein Secretases - Abstract
In an effort to improve physical properties by introducing polar functionality into the bicyclic pyrimidine gamma-secretase modulator (GSM) clinical candidate BMS-932481, we prepared several oxidative products of BMS-932481. Among the analogs that were prepared, the C-5 alcohol 3 was identified as the predominant metabolite of BMS-932481 found in rat and human liver microsomes. Alcohol 3 was determined to be chemically unstable, leading to the hypothesis that 3 may lead to the production of reactive species both in vitro and in vivo.
- Published
- 2020
21. Spiroannulation approach to pentalenene, an angular triquinane sesquiterpene
- Author
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Yong-Jin Wu, Yan-Yi Zhu, and Burnell, D. Jean
- Subjects
Terpenes -- Research ,Acylation -- Usage ,Ring formation (Chemistry) -- Analysis ,Biological sciences ,Chemistry - Abstract
Geminal acylation of the acetal of isophorone by 1, 2-bisubstituted cyclobutene in the presence of borontrifluoride etharate yields angular triquinane plus or minus pentalenene. The spiro (4.4) nonane system, required for the formation of the final central ring, was obtained through ring cleavage and reclosure. Reduction of the double bond and ketone and dehydration after cyclization to the enone completed the synthesis.
- Published
- 1994
22. Expedient Synthesis of Furo[2,3-d][1,3]thiazinamines and Pyrano[2,3-d][1,3]thiazinamines from Enones and Thiourea
- Author
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Lorin A. Thompson, Hyunsoo Park, Yong-Jin Wu, and Jason M. Guernon
- Subjects
0301 basic medicine ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,01 natural sciences ,0104 chemical sciences ,Ether formation ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,Thiourea ,Intramolecular force ,mental disorders ,Michael reaction ,Aminal ,Organic chemistry - Abstract
Michael addition of thiourea to enones with subsequent intramolecular aminal ether formation provided easy access to furo[2,3-d]thiazinamines and pyrano[2,3-d][1,3]thiazin-2-amines. These amines served as versatile intermediates to a variety of beta-amyloid cleaving enzyme-1 (BACE1) inhibitors.
- Published
- 2016
23. Synthesis of pyrimido[4,5- c ]azepine- and pyrimido[4,5- c ]oxepine-based γ-secretase modulators
- Author
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Lorin A. Thompson, Yunhui Zhang, Jeremy H. Toyn, John E. Macor, and Yong-Jin Wu
- Subjects
Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Metathesis ,01 natural sciences ,Biochemistry ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Discovery ,Humans ,Molecule ,Structure–activity relationship ,γ secretase ,Azepine ,Molecular Biology ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,010405 organic chemistry ,Organic Chemistry ,Azepines ,Combinatorial chemistry ,0104 chemical sciences ,Pyrimidines ,chemistry ,Oxepins ,biology.protein ,Molecular Medicine ,Amyloid Precursor Protein Secretases ,Amyloid precursor protein secretase ,030217 neurology & neurosurgery - Abstract
This Letter describes an efficient ring-closing metathesis approach to 2-chloro-4-amino-pyrimido[4,5-c]azepines and 2-chloro-4-amino-pyrimido[4,5-c]oxepines. These chlorides were applied to the synthesis of several potent γ-secretase modulators (GSMs).
- Published
- 2016
24. Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents
- Author
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Alicia Ng, Andrea McClure, Chiehying Chang, Fukang Yang, Hyunsoo Park, Yong-Jin Wu, Jason M. Guernon, Jianliang Shi, John E. Macor, Charles F. Albright, Ramkumar Rajamani, Michael K. Ahlijanian, Lorin A. Thompson, Jeremy H. Toyn, Lawrence B. Snyder, Hal A. Lewis, and Dan Camac
- Subjects
0301 basic medicine ,biology ,010405 organic chemistry ,Chemistry ,medicine.drug_class ,Organic Chemistry ,Active site ,Carboxamide ,Inhibitory postsynaptic potential ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Biochemistry of Alzheimer's disease ,Glutamine ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,mental disorders ,Drug Discovery ,biology.protein ,medicine ,Threonine ,Lead compound ,IC50 - Abstract
By targeting the flap backbone of the BACE1 active site, we discovered 6-dimethylisoxazole-substituted biaryl aminothiazine 18 with 34-fold improved BACE1 inhibitory activity over the lead compound 1. The cocrystal structure of 18 bound to the active site indicated two hydrogen-bond interactions between the dimethylisoxazole and threonine 72 and glutamine 73 of the flap. Incorporation of the dimethylisoxazole substitution onto the related aminothiazine carboxamide series led to pyrazine-carboxamide 26 as a very potent BACE1 inhibitor (IC50 < 1 nM). This compound demonstrated robust brain Aβ reduction in rat dose–response studies. Thus, compound 26 may be useful in testing the amyloid hypothesis of Alzheimer’s disease.
- Published
- 2016
25. Macrocyclic prolinyl acyl guanidines as inhibitors of β-secretase (BACE)
- Author
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Andrew C. Good, Joe Shi, Catherine R. Burton, Samuel Gerritz, John E. Macor, Weixu Zhai, Shirong Zhu, Richard E. Olson, Jeremy H. Toyn, James E. Grace, Donna M. Barten, Yunhui Zhang, Jere E. Meredith, Kimberley A. Lentz, Lorin A. Thompson, Yong-Jin Wu, Charles F. Albright, Jason M. Guernon, and Kenneth M. Boy
- Subjects
Male ,Macrocyclic Compounds ,Proline ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Cathepsin E ,Cathepsin D ,Guanidines ,Biochemistry ,Madin Darby Canine Kidney Cells ,Mice ,chemistry.chemical_compound ,Dogs ,In vivo ,Drug Discovery ,Animals ,Aspartic Acid Endopeptidases ,Humans ,Potency ,Protease Inhibitors ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Guanidine ,Molecular Biology ,chemistry.chemical_classification ,Isothiazole ,Amyloid beta-Peptides ,biology ,Chemotype ,Organic Chemistry ,Pepsin A ,Molecular Docking Simulation ,Enzyme ,chemistry ,biology.protein ,Molecular Medicine ,Efflux ,Amyloid Precursor Protein Secretases ,Caco-2 Cells ,Amyloid precursor protein secretase - Abstract
The synthesis, evaluation, and structure-activity relationships of a class of acyl guanidines which inhibit the BACE-1 enzyme are presented. The prolinyl acyl guanidine chemotype (7c), unlike compounds of the parent isothiazole chemotype (1), yielded compounds with good agreement between their enzymatic and cellular potency as well as a reduced susceptibility to P-gp efflux. Further improvements in potency and P-gp ratio were realized via a macrocyclization strategy. The in vivo profile in wild-type mice and P-gp effects for the macrocyclic analog 21c is presented.
- Published
- 2015
26. Discovery of furo[2,3- d ][1,3]thiazinamines as beta amyloid cleaving enzyme-1 (BACE1) inhibitors
- Author
-
Charles F. Albright, Yong-Jin Wu, Chiehying Chang, Jason M. Guernon, Michael K. Ahlijanian, Dan Camac, Jeremy H. Toyn, John E. Macor, Lorin A. Thompson, Jodi K. Muckelbauer, and Ramkumar Rajamani
- Subjects
Models, Molecular ,0301 basic medicine ,Amyloid ,Stereochemistry ,Clinical Biochemistry ,Thiazines ,Pharmaceutical Science ,01 natural sciences ,Biochemistry ,D-1 ,03 medical and health sciences ,chemistry.chemical_compound ,Alzheimer Disease ,Thiazine ,Catalytic Domain ,Amide ,Drug Discovery ,Hydrolase ,Aspartic Acid Endopeptidases ,Humans ,Enzyme Inhibitors ,Furans ,Molecular Biology ,chemistry.chemical_classification ,biology ,010405 organic chemistry ,Organic Chemistry ,Active site ,0104 chemical sciences ,030104 developmental biology ,Enzyme ,chemistry ,biology.protein ,Molecular Medicine ,Bioisostere ,Amyloid Precursor Protein Secretases ,Protein Binding - Abstract
This Letter describes the synthesis and structure-activity relationships of a series of furo[2,3-d][1,3]thiazinamine BACE1 inhibitors. The co-crystal structure of a representative thiazinamine 2e bound with the BACE1 active site displayed a binding mode driven by interactions with the catalytic aspartate dyad and engagement of the biaryl amide toward the S1 and S3 pockets. This work indicates that furo[2,3-d]thiazine can serve as a viable bioisostere of the known furo[3,4-d]thiazine.
- Published
- 2016
27. Survivin facilitates T-helper 2-biased inflammation in the airway
- Author
-
Mei-Zhen Zhao, Shan-Shan Li, Zhigang Liu, Ping-Chang Yang, Fei Ma, Li-Hua Mo, Jin-Mei Xue, Jiang-Qi Liu, Xian-Hai Zeng, Yong-Jin Wu, Tian-Yong Hu, Chang-Qing Zhao, and Rui-Di Xie
- Subjects
Adult ,Male ,Programmed cell death ,Allergy ,Survivin ,T-Lymphocytes ,Gene Expression ,Inflammation ,Pathogenesis ,Mice ,Th2 Cells ,Immunology and Allergy ,Medicine ,Animals ,Humans ,Interleukin 4 ,Mice, Knockout ,Cell Death ,business.industry ,medicine.disease ,Asthma ,Otorhinolaryngology ,Apoptosis ,Cancer research ,Female ,Interleukin-4 ,medicine.symptom ,Airway ,business - Abstract
Background The biased T helper 2 (Th2) responses play a critical role in the pathogenesis of allergy. The underlying mechanism is not fully understood yet. Survivin can regulate multiple cellular activities. This study aims to elucidate the role of survivin in the development and maintenance of Th2 polarization. Methods CD4+ T cells were isolated from blood samples collected from patients with allergic asthma (AS) and HS control (HS) subjects. Mice carrying CD4+ T cells with survivin knockout (KO mice) were employed to test the role of survivin in the development of the biased Th2 responses. Results KO mice failed to induce airway allergy. Peripheral CD4+ T cells expressed survivin, which was higher in the AS group than that in the HS group. Naive CD4+ T cells with higher expression of survivin were prone to differentiating into Th2 cells. Survivin bound to the Il4 promoter in CD4+ T cells to enhance Il4 gene transcription. The expression of Fas was lower in CD4+ T cells of the AS group than that in the HS group. Overexpression of survivin suppressed the expression of Fas and impaired the activation-induced cell death (AICD) of CD4+ T cells. Conclusion Survivin facilitates the development of biased Th2 polarization through promoting expression of interleukin 4 (IL-4) and impairing the AICD machinery of CD4+ T cells. To modulate the expression of survivin in CD4+ T cells has the translational potential in the treatment of allergic diseases.
- Published
- 2018
28. B cell lymphoma-2-like protein-12 association with T-helper 2 inflammation in chronic rhinosinusitis with allergy
- Author
-
Yun-Fang, An, Yong-Jin, Wu, Xian-Hai, Zeng, Li-Juan, Song, Fei, Ma, Wen-Jing, Liao, Zhi-Qiang, Liu, Gui, Yang, Xiao-Wen, Zhang, Zhi-Gang, Liu, Chang-Qing, Zhao, and Ping-Chang, Yang
- Subjects
Adult ,Male ,Nasal Mucosa ,Th2 Cells ,Proto-Oncogene Proteins c-bcl-2 ,Chronic Disease ,Hypersensitivity ,Cytokines ,Humans ,Muscle Proteins ,Female ,Sinusitis ,Rhinitis - Abstract
T-helper 2 (Th2) polarization plays a critical role in the pathogenesis of chronic rhinosinusitis (CRS) with accompanying nasal allergy. Recent studies indicate that B cell lymphoma-2-like protein-12 (Bcl2L12) is associated with immune dysregulation. The purpose of this study was to elucidate the role of Bcl2L12 in the pathogenesis of Th2 polarization of CRS patients.CRS patients with nasal allergy (CRSa) and without nasal allergy (CRSna) were recruited into this study. CD4Twenty CRSa patients, 20 CRSna patients, and 20 healthy subjects were recruited into this study. High levels of immunoglobulin E (IgE), interleukin 4 (IL-4), IL-5, IL-13, and Bcl2L12 were detected in nasal extracts of CRSa patients, but not in CRSna patients. The levels of Bcl2L12 were positively correlated with Th2 cytokines. CD4Bcl2L12 is positively correlated with Th2 cytokine levels in the nasal mucosa of CRSa patients. Bcl2L12 contributes to the Th2 polarization, which may be a novel therapeutic target in the treatment of CRSa.
- Published
- 2018
29. Discovery and characterization of N-(1,3-dialkyl-1H-indazol-6-yl)-1H-pyrazolo[4,3-b]pyridin-3-amine scaffold as mGlu
- Author
-
Darren W, Engers, Sean R, Bollinger, Julie L, Engers, Joseph D, Panarese, Megan M, Breiner, Alison, Gregro, Anna L, Blobaum, Joanne J, Bronson, Yong-Jin, Wu, John E, Macor, Alice L, Rodriguez, Rocio, Zamorano, P Jeffrey, Conn, Craig W, Lindsley, Colleen M, Niswender, and Corey R, Hopkins
- Subjects
Antiparkinson Agents ,Structure-Activity Relationship ,Allosteric Regulation ,Cytochrome P-450 CYP1A2 ,Pyridines ,Enzyme Induction ,Cytochrome P-450 CYP1A2 Inducers ,Drug Discovery ,Animals ,Humans ,Pyrazoles ,Receptors, Metabotropic Glutamate ,Rats - Abstract
Previous reports from our laboratory disclosed the structure and activity of a novel 1H-pyrazolo[4,3-b]pyridine-3-amine scaffold (VU8506) which showed excellent potency, selectivity and in vivo efficacy in preclinical rodent models of Parkinson's disease. Unfortunately, this compound suffered from significant CYP1A2 induction as measured through upstream AhR activation (125-fold) and thus was precluded from further advancement in chronic studies. Herein, we report a new scaffold developed recently which was systematically studied in order to mitigate the CYP1A2 liabilities presented in the earlier scaffolds. We have identified a novel structure that maintains the potency and selectivity of other mGlu
- Published
- 2018
30. Bcl2L12 plays a critical role in the development of intestinal allergy
- Author
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Jiang-Qi Liu, Yong-Jin Wu, Bai-Sui Feng, Ping-Chang Yang, Xiao-Rui Geng, Jing-Yi Hong, Peng-Yuan Zheng, and Zhigang Liu
- Subjects
0301 basic medicine ,Adult ,Male ,Adoptive cell transfer ,Allergy ,T cell ,Immunology ,Muscle Proteins ,Inflammation ,GATA3 Transcription Factor ,medicine.disease_cause ,Pathogenesis ,03 medical and health sciences ,Mice ,Th2 Cells ,medicine ,Immunology and Allergy ,Animals ,Humans ,Intestinal Mucosa ,Promoter Regions, Genetic ,Interleukin 4 ,Mice, Knockout ,Mice, Inbred BALB C ,Chemistry ,GATA3 ,medicine.disease ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Proto-Oncogene Proteins c-bcl-2 ,Allergic response ,Female ,Interleukin-4 ,medicine.symptom ,Food Hypersensitivity - Abstract
The skewed T helper (Th) 2 response plays a central role in the pathogenesis of allergic diseases, while its initiating factors remain elusive. Recent studies indicate that Bcl2 like protein-12 (Bcl2L12) is associated with the Th2-biased inflammation. This study is designed to test a hypothesis that Bcl2L12 plays a critical role in the initiation of allergic response. In this study, peripheral CD4+ T cells were isolated from food allergy (FA) patients and healthy subjects; A mouse FA model was developed to test the role of Bcl2L12 in induction of allergic response in the intestine. The results showed that expression of Bcl2L12 by CD4+ T cells was higher in FA patients and FA mice and positively correlated with expression of Th2 cytokines. CD4+ T cells from FA patients showed a Bcl2L12-dependent tendency to differentiate into Th2 cells. Bcl2L12 played a crucial role in induction of allergic response in the intestine. Physical contact between Bcl2L12 and GATA3 facilitated GATA3 to bind Il4 promoter to promote expression of IL-4. Adoptive transfer with Bcl2L12-deficient CD4+ T cells to Rag2¯/¯ mice did not reconstitute the efficient CD4+ T cell response as the mice could not be induced FA, while Rag2¯/¯ mice received WT CD4+ T cell transfer were induced FA. In conclusion, Bcl2L12 plays a crucial role in the induction of Th2 polarization and allergic response in the intestine. The Bcl2L12 in CD4+ T cells may be a potential target for the treatment of FA.
- Published
- 2018
31. Bcl2L12 mediates effects of protease-activated receptor-2 on the pathogenesis of Th2-dominated responses of patients with ulcerative colitis
- Author
-
Zhigang Liu, Xian-Hai Zeng, Dian Yu, Cai-Jie Zhou, Ping-Chang Yang, Bai-Sui Feng, Zhi-Qiang Liu, Yong-Jin Wu, and Peng-Yuan Zheng
- Subjects
0301 basic medicine ,Adult ,CD4-Positive T-Lymphocytes ,Male ,Colon ,Biophysics ,Muscle Proteins ,Inflammation ,GATA3 Transcription Factor ,medicine.disease_cause ,Biochemistry ,Receptors, G-Protein-Coupled ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Th2 Cells ,Immunity ,medicine ,Animals ,Humans ,Receptor, PAR-2 ,Intestinal Mucosa ,Promoter Regions, Genetic ,Molecular Biology ,Interleukin 4 ,Protease-activated receptor 2 ,Mice, Knockout ,Mice, Inbred BALB C ,business.industry ,GATA3 ,Immune dysregulation ,medicine.disease ,Ulcerative colitis ,030104 developmental biology ,Proto-Oncogene Proteins c-bcl-2 ,030220 oncology & carcinogenesis ,Cancer research ,Cytokines ,Colitis, Ulcerative ,Female ,medicine.symptom ,business - Abstract
The immune dysregulation plays an important role in the pathogenesis of ulcerative colitis (UC). Bcl2 like protein-12 (Bcl2L12) and mast cells are involved in immune dysregulation of UC. This study aims to elucidate the role of Bcl2L12 in the contribution to the pathogenesis of T helper (Th)2-biased inflammation in UC patients. The results showed that Bcl2L12 was expressed by peripheral CD4+ T cells that was associated with Th2 polarization in UC patients. Bcl2L12 mediated the protease-activated receptor-2 (PAR2)-induced IL-4 expression in CD4+ cells. Activation of PAR2 increased expression of Bcl2L12 in CD4+ T cells. Bcl2L12 mRNA decayed spontaneously in CD4+ T cells after separated from UC patients which was prevented by activating PAR2. Bcl2L12 mediated the binding between GATA3 and the Il4 promoter in CD4+ T cells. Mice with Bcl2L12 deficiency failed to induce Th2-biased inflammation in the colon mucosa. We conclude that CD4+ T cells from UC patients expressed high levels of Bcl2L12; the latter plays an important role in the development of Th2-biased inflammation in the intestine. Bcl2L12 may be a novel therapeutic target in the treatment of Th2-biased inflammation.
- Published
- 2018
32. Histone deacetylase 11 inhibits interleukin 10 in B cells of subjects with allergic rhinitis
- Author
-
Jian-Bo, Shao, Xiang-Qian, Luo, Yong-Jin, Wu, Mao-Gang, Li, Jing-Yi, Hong, Li-Hua, Mo, Zhi-Gang, Liu, Hua-Bin, Li, Da-Bo, Liu, and Ping-Chang, Yang
- Subjects
Adult ,Male ,B-Lymphocytes ,Mice, Inbred BALB C ,Immunoglobulin E ,Rhinitis, Allergic ,Histone Deacetylases ,Young Adult ,Animals ,Cytokines ,Humans ,Female ,Cells, Cultured ,Spleen - Abstract
The interleukin (IL)-10 expression in B cells plays an important role in immune tolerance. The regulation of IL-10 expression in B cells is not fully understood yet. Tumor necrosis factor (TNF) is increased in allergic rhinitis (AR) patients. This study tests a hypothesis that TNF enhances histone deacetylase (HDAC)11 expression to inhibit the expression of IL-10 in B cells of AR patients.Peripheral B cells were collected from healthy persons and patients with AR. The B cells were analyzed by immune assay and molecular biological approaches for the expression of IL-10.The expression of HDAC11 was higher in B cells of patients with AR than that in healthy persons. The expression of IL-10 in B cells was lower in AR patients than that in healthy subjects. The levels of HDAC11 in B cells were negatively correlated with the levels of IL-10. Exposure of B cells to TNF in the culture inhibited the expression of IL-10, in which HDAC11 played a critical role in the interference with the Il10 gene transcription. Inhibition of HDAC11 restored the IL-10 expression in B cells from AR patients and attenuated the experimental AR.TNF can suppress the expression of IL-10 in B cells via enhancing the expression of HDAC11. Inhibition of HDAC11 restores the IL-10 expression in B cells of AR subjects. HDAC11 may be a novel target for the treatment of AR.
- Published
- 2018
33. Discovery of morpholine-based aryl sulfonamides as Na
- Author
-
Yong-Jin, Wu, Jason, Guernon, Andrea, McClure, Brian, Venables, Ramkumar, Rajamani, Kevin J, Robbins, Ronald J, Knox, Michele, Matchett, Rick L, Pieschl, James, Herrington, Linda J, Bristow, Nicholas A, Meanwell, Richard, Olson, Lorin A, Thompson, and Carolyn, Dzierba
- Subjects
Voltage-Gated Sodium Channel Blockers ,Structure-Activity Relationship ,Sulfonamides ,Dose-Response Relationship, Drug ,Molecular Structure ,Morpholines ,NAV1.7 Voltage-Gated Sodium Channel ,Humans - Abstract
Replacement of the piperidine ring in the lead benzenesulfonamide Na
- Published
- 2017
34. Discovery of non-zwitterionic aryl sulfonamides as Na
- Author
-
Yong-Jin, Wu, Jason, Guernon, Andrea, McClure, Guanglin, Luo, Ramkumar, Rajamani, Alicia, Ng, Amy, Easton, Amy, Newton, Clotilde, Bourin, Dawn, Parker, Kathleen, Mosure, Omar, Barnaby, Matthew G, Soars, Ronald J, Knox, Michele, Matchett, Rick, Pieschl, James, Herrington, Ping, Chen, D V, Sivarao, Linda J, Bristow, Nicholas A, Meanwell, Joanne, Bronson, Richard, Olson, Lorin A, Thompson, and Carolyn, Dzierba
- Subjects
Inflammation ,Male ,Neurons ,Nociception ,Sulfonamides ,Dose-Response Relationship, Drug ,Molecular Structure ,Freund's Adjuvant ,NAV1.7 Voltage-Gated Sodium Channel ,Administration, Oral ,Models, Biological ,Disease Models, Animal ,Mice ,Structure-Activity Relationship ,HEK293 Cells ,Drug Discovery ,Animals ,Humans ,Chronic Pain - Abstract
Since zwitterionic benzenesulfonamide Na
- Published
- 2017
35. Development of New Benzenesulfonamides As Potent and Selective Na
- Author
-
Yong-Jin, Wu, Jason, Guernon, Jianliang, Shi, Jonathan, Ditta, Kevin J, Robbins, Ramkumar, Rajamani, Amy, Easton, Amy, Newton, Clotilde, Bourin, Kathleen, Mosure, Matthew G, Soars, Ronald J, Knox, Michele, Matchett, Rick L, Pieschl, Debra J, Post-Munson, Shuya, Wang, James, Herrington, John, Graef, Kimberly, Newberry, Linda J, Bristow, Nicholas A, Meanwell, Richard, Olson, Lorin A, Thompson, and Carolyn, Dzierba
- Subjects
Male ,Voltage-Gated Sodium Channel Blockers ,Analgesics ,Mice ,Sulfonamides ,HEK293 Cells ,Piperidines ,Ganglia, Spinal ,Drug Discovery ,NAV1.7 Voltage-Gated Sodium Channel ,Animals ,Humans ,Pain - Abstract
By taking advantage of certain features in piperidine 4, we developed a novel series of cyclohexylamine- and piperidine-based benzenesulfonamides as potent and selective Na
- Published
- 2017
36. Synthesis of β-disubstituted β-amino isoxazolyl ketones by addition of ketimines with isoxazolyl methyl ketone enolates
- Author
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Mendi A. Higgins, Jianliang Shi, Lawrence R. Marcin, Yong-Jin Wu, Jason M. Guernon, Fukang Yang, Lorin A. Thompson, and Lawrence B. Snyder
- Subjects
Chemistry ,Methyl Ketone ,Organic Chemistry ,Drug Discovery ,Biochemistry ,Medicinal chemistry - Abstract
A series of β-disubstituted N-sulfinyl β-amino isoxazolyl ketones has been prepared by addition of tert-butanesulfinyl ketimines with the n-BuLi-generated enolates of isoxazolyl methyl ketones.
- Published
- 2014
37. 3-Methyl-4-nitrophenol triggers nasal allergy by modulating dendritic cell properties
- Author
-
Li-Teng Yang, Xiaowen Zhang, Xiaoyu Liu, Yong-Jin Wu, Rui-Di Xie, Zhigang Liu, Jiang-Qi Liu, Xian-Hai Zeng, Xiao-Rui Geng, Lijuan Song, Li-Hua Mo, Ping-Chang Yang, and Shuai Wang
- Subjects
Male ,Antigen Presentation ,Mice, Inbred BALB C ,Chemistry ,Immunology ,Bone Marrow Cells ,Dendritic Cells ,Nasal allergy ,Dendritic cell ,Rhinitis, Allergic ,Cresols ,Mice ,Nasal Mucosa ,Animals ,Immunology and Allergy ,Cells, Cultured - Published
- 2019
38. Discovery of (S,E)-3-(2-fluorophenyl)-N-(1-(3-(pyridin-3-yloxy)phenyl)ethyl)-acrylamide as a potent and efficacious KCNQ2 (Kv7.2) opener for the treatment of neuropathic pain
- Author
-
Vincenzo Calandra, Steven I. Dworetzky, Yong-Jin Wu, Ronald J. Knox, William Fitzpatrick, Huan He, JoAnne E Natale, David G. Harden, Li-Qiang Sun, Carl D. Davis, David Weaver, Frederic Machet, Joseph Polino, John E. Starrett, Karen Heman, Ping Chen, Valentin K. Gribkoff, Christopher G. Boissard, Clotilde Bourin, Charles M. Conway, Jie Chen, and Mark W. Thompson
- Subjects
Male ,Acrylamides ,Formalin Test ,Patch-Clamp Techniques ,Diabetic neuropathy ,Chemistry ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Pharmacology ,medicine.disease ,Biochemistry ,Rats ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Acrylamide ,Drug Discovery ,Neuropathic pain ,medicine ,Animals ,KCNQ2 Potassium Channel ,Neuralgia ,Molecular Medicine ,Molecular Biology - Abstract
Acrylamide (S)-6, a potent and efficacious KCNQ2 (Kv7.2) opener, demonstrated significant activity in two models of neuropathic pain and in the formalin test, suggesting that KCNQ2 openers may be useful in the treatment of neuropathic pain including diabetic neuropathy.
- Published
- 2013
39. 2,5-Bis-(sulfonyl)pyrazines as unprecedented building blocks and their SNAr reactions
- Author
-
Wei Meng, Jie Jack Li, Shung Wu, Yong-Jin Wu, Jason M. Guernon, Bang-Chi Chen, Martin Patrick Allen, Peter T. W. Cheng, and Michael M. Miller
- Subjects
Sulfonyl ,chemistry.chemical_classification ,Pyrazine ,Organic Chemistry ,chemistry.chemical_element ,Biochemistry ,Medicinal chemistry ,chemistry.chemical_compound ,Malonate ,Nucleophile ,chemistry ,Nucleophilic aromatic substitution ,Drug Discovery ,Phenols ,Carbon - Abstract
Previously unknown 2,5-bis-sulfonylpyrazines are prepared and their S N Ar reactions are investigated. When 2 equiv of thiols are employed, the corresponding bis-thiopyrazines are obtained exclusively. However, phenols or alkoxides gave rise to only the corresponding mono-substituted aryloxy- or alkoxy-sulfonylpyrazines in excellent yields. A carbon nucleophile prepared by treating malonate with NaH also produced the corresponding mono-sulfonylpyrazines. Aliphatic amines and anilines only provided the mono-anilino-sulfonylpyrazines in poor to moderate yields.
- Published
- 2013
40. Five-Membered Ring Systems
- Author
-
Yong-Jin Wu
- Subjects
Isothiazole ,010405 organic chemistry ,Chemistry ,Thiazoline ,Atom (order theory) ,chemistry.chemical_element ,010402 general chemistry ,Ring (chemistry) ,01 natural sciences ,Medicinal chemistry ,Sulfur ,0104 chemical sciences ,chemistry.chemical_compound ,Benzothiazole ,Thiadiazoles ,Organic chemistry ,Thiazole - Abstract
This review chapter describes the syntheses and reactions of five-membered heterocyclic ring systems containing nitrogen and sulfur (reported during 2015). The importance of these p-rich heterocycles in medicinal chemistry and natural products is also covered.
- Published
- 2016
41. Facial Selectivity in the Diels-Alder Reactions of 2,2-Disubstituted Cyclopent-4-ene-1,3-dione Derivatives and a Computational Examination of the Facial Selectivity of the Diels-Alder Reactions of Structurally Related Dienes and Dienophiles
- Author
-
Paul D. Thornton, D. Jean Burnell, Cory C. Pye, Yong-Jin Wu, Raymond A. Poirier, and Pei-Ying Liu
- Subjects
Steric effects ,chemistry.chemical_compound ,Bicyclic molecule ,chemistry ,Stereochemistry ,Organic Chemistry ,Cyclopentene ,Physical and Theoretical Chemistry ,Selectivity ,Ene reaction ,Cycloaddition ,Transition state ,Octane - Abstract
The facial selectivity in the Diels–Alder reactions via endo transition states of the plane-nonsymmetric dienophiles spiro[bicyclo[2.2.2]octane-2,1′-[3]cyclopentene]-2′,5′-dione (6) and spiro[bicyclo[2.2.1]heptane-2,1′-[3]cyclopentene]-2′,5′-dione (7) has been found to be very similar to the facial selectivity of reactions of cyclopentadienes fused to bicyclo[2.2.2]octane and bicyclo[2.2.1]heptane (4 and 5). This is strong evidence for steric control in their facial selectivities. Density functional computations involving the reactions of these compounds, as well as a series of conformationally locked model addends (26a–c and 27a–c), revealed geometrical and energetic properties that confirmed that the facial selectivity is governed by steric effects. Steric interactions appeared to be the reason for the low endo/exo selectivity of dienophiles 6, 7, 2,2-dimethylcyclopent-4-ene-1,3-dione (20), and spiro[5.4]dec-8-ene-7,10-dione (23).
- Published
- 2011
42. Study on Damage Parameters and its Size Effect of Concrete by Tension Test
- Author
-
Xi Hua, Yue Feng Wang, Yong Jin Wu, Xiang Dong Wang, and Yan Wang
- Subjects
Materials science ,Mechanics of Materials ,Tension (physics) ,business.industry ,Mechanical Engineering ,Carrying capacity ,General Materials Science ,Structural engineering ,Peak value ,Composite material ,business ,Elastic modulus ,Tensile testing - Abstract
The carrying capacity decreases continuously as the material property deteriorates under the action of some external factors. It is important to evaluate the damage of concrete, in which the damage parameter plays an important role. An experimentation method is designed in this paper, with which we can simulate the initial damage by mixing initiator into concrete. Using the elastic modulus of axial tension experimentation, the tension initial damage D0 and tension damage Peak value Df have been gained. The Size effect of concrete tension damage parameters is verified. The curve of damage-parameters and size is gained, the trend of the tension damage parameters is obtained.
- Published
- 2011
43. Efficient synthesis of (Z)- and (E)-methyl 2-(methoxyimino)-2-phenylacetate
- Author
-
Yong-Jin Wu, S. Roy Kimura, Stella Huang, Qi Gao, Alicia Ng, and David R. Langley
- Subjects
chemistry.chemical_compound ,Phenylacetate ,chemistry ,Yield (chemistry) ,Organic Chemistry ,Drug Discovery ,Organic chemistry ,Oxime ,Biochemistry ,Isomerization - Abstract
Direct oximation of 2-oxo-2-phenylacetate (3) gave the (Z)-methyl 2-(methoxyimino)-2-phenylacetate (1) in 71% yield, while the E oxime 2 was prepared from 3 in 65% yield via oxime isomerization of 2-(methoxyimino)-2-phenylacetic acid (5). Computational studies suggest that the isomerization of 5 is thermodynamically driven, while the direct oximation of ketoester 3 is kinetically controlled.
- Published
- 2010
44. Synthesis and SAR of hydroxyethylamine based phenylcarboxyamides as inhibitors of BACE
- Author
-
Yunhui Zhang, John E. Macor, Lorin A. Thompson, Jeremy H. Toyn, Andrew C. Good, Catherine R. Burton, Yong-Jin Wu, and Charles F. Albright
- Subjects
Molecular model ,medicine.drug_class ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Carboxamide ,Transfection ,Biochemistry ,Chemical synthesis ,Cell Line ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Humans ,Protease Inhibitors ,Molecular Biology ,biology ,Chemistry ,Organic Chemistry ,Enzyme inhibitor ,Benzamides ,β secretase ,biology.protein ,Molecular Medicine ,Amyloid Precursor Protein Secretases ,Aspartic Endopeptidases - Abstract
A series of N-((2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-(3-methoxybenzylamino)-butan-2-yl)benzamides has been synthesized as BACE inhibitors. A variety of P2 and P3 substituents has been explored, and these efforts have culminated in the identification of several 1,3,5-trisubstituted phenylcarboxyamides with potent BACE inhibitory activity.
- Published
- 2009
45. (S,E)-N-[1-(3-Heteroarylphenyl)ethyl]-3-(2-fluorophenyl)acrylamides: synthesis and KCNQ2 potassium channel opener activity
- Author
-
Alain Martel, Li-Qiang Sun, Jie Chen, Huan He, Ronald J. Knox, David G. Harden, JoAnne E Natale, Steven I. Dworetzky, Yong-Jin Wu, Alexandre L'Heureux, David Weaver, John E. Starrett, and Mark W. Thompson
- Subjects
Stereochemistry ,medicine.drug_class ,Clinical Biochemistry ,Action Potentials ,Pharmaceutical Science ,Carboxamide ,Biochemistry ,Chemical synthesis ,Cell Line ,chemistry.chemical_compound ,KCNQ2 Potassium Channel ,Drug Discovery ,medicine ,Animals ,Humans ,Moiety ,Molecular Biology ,Acrylamides ,Dose-Response Relationship, Drug ,Molecular Structure ,Organic Chemistry ,chemistry ,Potassium Channels, Voltage-Gated ,Acrylamide ,Benzene derivatives ,Molecular Medicine - Abstract
Replacement of the morpholinyl moiety in (S,E)-N-[1-(3-morpholinophenyl)ethyl]-3-phenylacrylamide (1) with heteroaryl groups led to the identification of (S,E)-N-1-[3-(6-fluoropyridin-3-yl)phenyl]ethyl-3-(2-fluorophenyl)acrylamide (5) as a potent KCNQ2 potassium channel opener. Among this series of heteroaryl substituted acrylamides, (S,E)-N-1-[3-(1H-pyrazol-1-yl)phenyl]ethyl-3-(2-fluorophenyl)acrylamide (9) exhibits balanced potency and efficacy. The syntheses and the KCNQ2 opener activity of this series of acrylamides are described.
- Published
- 2005
46. Synthesis and KCNQ2 opener activity of N-(1-benzo[1,3]dioxol-5-yl-ethyl, N-[1-(2,3-dihydro-benzofuran-5-yl)-ethyl, and N-[1-(2,3-dihydro-1H-indol-5-yl)-ethyl acrylamides
- Author
-
Jean-Paul Daris, John E. Starrett, Pierre Dextraze, Rick L. Pieschl, Huan He, David G. Harden, David Weaver, Jie Chen, Yong-Jin Wu, Ronald J. Knox, Valentin K. Gribkoff, Li-Qiang Sun, Qi Gao, Mark W. Thompson, Dedong Wu, Christopher G. Boissard, Steven I. Dworetzky, William Fitzpatrick, and JoAnne E Natale
- Subjects
Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Hippocampus ,Biochemistry ,Chemical synthesis ,Cell Line ,chemistry.chemical_compound ,Drug Discovery ,Animals ,Humans ,KCNQ2 Potassium Channel ,Potency ,Benzofuran ,Molecular Biology ,Benzofurans ,Acrylamides ,Dose-Response Relationship, Drug ,Organic Chemistry ,Biological activity ,Rats ,chemistry ,Potassium Channels, Voltage-Gated ,Acrylamide ,Neuronal Hyperexcitability ,Molecular Medicine ,Bioisostere ,Enantiomer - Abstract
Bioisosteric replacement studies led to the identification of N -(1-benzo[1,3]dioxol-5-yl-ethyl)-3-(2-chloro-phenyl)-acrylamide (( S )- 3 ) as a highly potent KCNQ2 opener, and 3-(2,6-difluoro-phenyl)- N -[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-acrylamide (( S )- 4 ), and N -[1-(2,3-dihydro-1 H -indol-5-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide (( S )- 5 ) as highly efficacious KCNQ2 openers. In contrast, their respective R enantiomers showed significantly less or no appreciable KCNQ2 opener activity even at the highest concentration tested (10 μM). Because of its high potency and moderate efficacy as well as its convenient synthesis, (±)- 3 was selected as a reference compound for analyzing efficacies of KCNQ openers in electrophysiology studies. Compounds ( S )- 4 and ( S )- 5 demonstrated significant activity in reducing neuronal hyperexcitability in rat hippocampal slices. The synthesis and the KCNQ2 opener activity of these acrylamides are described.
- Published
- 2004
47. Synthesis and Structure−Activity Relationship of Acrylamides as KCNQ2 Potassium Channel Openers
- Author
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Li-Qiang Sun, John E. Starrett, Pierre Dextraze, Steven I. Dworetzky, Jie Chen, Valentin K. Gribkoff, JoAnne E Natale, Alexandre L'Heureux, Huan He, Yong-Jin Wu, and Christopher G. Boissard
- Subjects
Patch-Clamp Techniques ,Potassium Channels ,Stereochemistry ,Morpholines ,Chemical synthesis ,Mice ,Structure-Activity Relationship ,Xenopus laevis ,KCNQ2 Potassium Channel ,Drug Discovery ,Animals ,Humans ,Structure–activity relationship ,Patch clamp ,Acrylamides ,Voltage-gated ion channel ,Chemistry ,Cortical Spreading Depression ,Stereoisomerism ,Potassium channel ,Cinnamates ,Potassium Channels, Voltage-Gated ,Cortical spreading depression ,Oocytes ,Molecular Medicine ,Pharmacophore - Abstract
A new class of acrylamides was synthesized, and the effects of these analogues on outward potassium current were evaluated by using two electrode voltage clamp recordings from Xenopus laevis oocytes expressing cloned mKCNQ2 channels. SAR studies indicated that the pharmacophore of the acrylamide series includes the (S) absolute configuration at the (1-phenyl)ethyl moiety and the alpha,beta-unsaturated acrylamide functionality with a free NH. This study identified (S)-N-[1-(3-morpholin-4-yl-phenyl)-ethyl]-3-phenyl-acrylamide ((S)-1) and (S)-N-[1-(4-fluoro-3-morpholin-4-yl-phenyl)-ethyl]-3-(4-fluoro-phenyl)-acrylamide ((S)-2) as KCNQ2 openers for further electrophysiological evaluations. These two acrylamides demonstrated significant activity in the cortical spreading depression model of migraine as we reported previously.
- Published
- 2004
48. (S)-N-[1-(4-Cyclopropylmethyl-3,4-dihydro-2H-benzooxazin-6-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide is a potent and efficacious KCNQ2 opener which inhibits induced hyperexcitability of rat hippocampal neurons
- Author
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Christopher G. Boissard, Huan He, David Weaver, Valentin K. Gribkoff, David G. Harden, Jie Chen, Qi Gao, Mark W. Thompson, Li-Qiang Sun, Dedong Wu, William Fitzpatrick, JoAnne E Natale, John E. Starrett, Yong-Jin Wu, Rick L. Pieschl, Ronald J. Knox, and Steven I. Dworetzky
- Subjects
Bicyclic molecule ,medicine.drug_class ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Central nervous system ,Pharmaceutical Science ,Carboxamide ,Hippocampal formation ,Biochemistry ,Chemical synthesis ,Linopirdine ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,Acrylamide ,Drug Discovery ,medicine ,Molecular Medicine ,Neuron ,Molecular Biology ,medicine.drug - Abstract
(S)-N-[1-(4-Cyclopropylmethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide ((S)-2) was identified as a potent and efficacious KCNQ2 opener. This compound demonstrated significant activity in reducing neuronal hyperexcitability in rat hippocampal slices, and the inhibition mediated by (S)-2 was reversed by the KCNQ blocker linopirdine.
- Published
- 2004
49. Fluorine Substitution Can Block CYP3A4 Metabolism-Dependent Inhibition: Identification of (S)-N-[1-(4-Fluoro-3- morpholin-4-ylphenyl)ethyl]-3- (4-fluorophenyl)acrylamide as an Orally Bioavailable KCNQ2 Opener Devoid of CYP3A4 Metabolism-Dependent Inhibition
- Author
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Zoeckler Mary Edson, Digavalli V. Sivarao, Thomas Philip, David Weaver, Li-Qiang Sun, Carl D. Davis, Steven I. Dworetzky, Amy Newton, Huan He, David G. Harden, Craig Polson, Ronald J. Knox, Yong-Jin Wu, Michael Sinz, Suresh Yeola, William Fitzpatrick, and Svetlana Tertyshnikova
- Subjects
Male ,Patch-Clamp Techniques ,Potassium Channels ,medicine.drug_class ,Stereochemistry ,Migraine Disorders ,Morpholines ,Reactive intermediate ,Administration, Oral ,Biological Availability ,Stereoisomerism ,Carboxamide ,Chemical synthesis ,Cell Line ,Membrane Potentials ,Rats, Sprague-Dawley ,Structure-Activity Relationship ,chemistry.chemical_compound ,Oral administration ,Parietal Lobe ,Drug Discovery ,medicine ,Animals ,Cytochrome P-450 CYP3A ,Cytochrome P-450 Enzyme Inhibitors ,KCNQ2 Potassium Channel ,Structure–activity relationship ,Chemistry ,Biological activity ,Fluorine ,Rats ,Disease Models, Animal ,Cinnamates ,Potassium Channels, Voltage-Gated ,Acrylamide ,Injections, Intravenous ,Molecular Medicine ,Ion Channel Gating - Abstract
The formation of a reactive intermediate was found to be responsible for CYP3A4 metabolism-dependent inhibition (MDI) observed with (S)-N-[1-(3-morpholin-4-ylphenyl)ethyl]-3-phenyl-acrylamide (1). Structure-3A4 MDI relationship studies culminated in the discovery of a difluoro analogue, (S)-N-[1-(4-fluoro-3-morpholin-4-ylphenyl)ethyl]-3-(4-fluoro-phenyl)acrylamide (2), as an orally bioavailable KCNQ2 opener free of CYP3A4 MDI.
- Published
- 2003
50. (S)-N-[1-(3-Morpholin-4-ylphenyl)ethyl]- 3-phenylacrylamide: An Orally Bioavailable KCNQ2 Opener with Significant Activity in a Cortical Spreading Depression Model of Migraine
- Author
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Shing Hong Kang, Svetlana Tertyshnikova, Michael Sinz, Sanna Lehtinen-Oboma, John E. Starrett, Yong-Jin Wu, Steven I. Dworetzky, Alexandre L'Heureux, Digavalli V. Sivarao, Mark W. Thompson, Gene G. Kinney, Christopher G. Boissard, Amy Newton, David Weaver, Henry S. Wong, Ronald J. Knox, Valentin K. Gribkoff, Li-Qiang Sun, Lei Zhang, JoAnne E Natale, Corinne R. Greco, Huan He, and David G. Harden
- Subjects
Patch-Clamp Techniques ,Potassium Channels ,Stereochemistry ,Migraine Disorders ,Morpholines ,Potassium ,Administration, Oral ,Biological Availability ,chemistry.chemical_element ,Pharmacology ,Cell Line ,Rats, Sprague-Dawley ,Structure-Activity Relationship ,Xenopus laevis ,Dogs ,Pharmacokinetics ,Oral administration ,KCNQ2 Potassium Channel ,Drug Discovery ,medicine ,Animals ,Humans ,Cerebral Cortex ,Acrylamides ,Chemistry ,Stereoisomerism ,Biological activity ,medicine.disease ,Rats ,Bioavailability ,Disease Models, Animal ,Migraine ,Potassium Channels, Voltage-Gated ,Cortical spreading depression ,Oocytes ,Molecular Medicine ,Ion Channel Gating - Abstract
(S)-N-[1-(3-Morpholin-4-ylphenyl)ethyl]-3-phenylacrylamide (2) was synthesized as an orally bioavailable KCNQ2 potassium channel opener. In a rat model of migraine, 2 demonstrated significant oral activity in reducing the total number of cortical spreading depressions induced by potassium chloride.
- Published
- 2003
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