Development of a Series of (1-Benzyl-3-(6-methoxypyrimidin-3-yl)-5-(trifluoromethoxy)-1H-indol-2-yl)methanols as Selective Protease Activated Receptor 4 (PAR4) Antagonists with in Vivo Utility and Activity Against γ-Thrombin
| Autor: | Summer E. Young, Shaun R. Stauffer, Kayla J. Temple, Craig W. Lindsley, Wandong Wen, Matthew T. Duvernay, Jae G. Maeng, Anna L. Blobaum, Wenjun Wu, Heidi E. Hamm |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Indoles Stereochemistry 030204 cardiovascular system & hematology Article Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Thrombin In vivo Drug Discovery medicine Humans Potency Enzyme Inhibitors IC50 Indole test Dose-Response Relationship Drug Molecular Structure Chemistry In vitro Pyrimidines 030104 developmental biology cardiovascular system Molecular Medicine PROTEASE-ACTIVATED RECEPTOR 4 Receptors Thrombin Selectivity medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 59:7690-7695 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.6b00928 |
| Popis: | Here, we describe the development of a series of highly selective PAR4 antagonists with nanomolar potency and selectivity versus PAR1, derived from the indole-based 3. Of these, 9j (PAR4 IC50 = 445 nM, PAR1 response IC50 > 30 µM) and 10h (PAR4 IC50 = 179 nM, PAR1 response IC50 > 30 µM) maintained an overall favorable in vitro DMPK profile, encouraging rat/mouse in vivo pharmacokinetics (PK) and activity against γ-thrombin. |
| Databáze: | OpenAIRE |
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