Development of a Series of (1-Benzyl-3-(6-methoxypyrimidin-3-yl)-5-(trifluoromethoxy)-1H-ind ol-2-yl)methanols as Selective Protease Activated Receptor 4 (PAR4) Antagonists with in Vivo Utility and Activity Against γ-Thrombin

作者：Temple, Kayla J.; Duvernay, Matthew T.; Young, Summer E.; Wen, Wandong; Wu, Wenjun; Maeng, Jae G.; Blobaum, Anna L.; Stauffer, Shaun R.; Hamm, Heidi E.^*; Lindsley, Craig W.^*

来源：Journal of Medicinal Chemistry, 2016, 59(16): 7690-7695.

DOI：10.1021/acs.jmedchem.6b00928

• ST-SEGMENT ELEVATION
• ACUTE CORONARY SYNDROMES
• MYOCARDIAL-INFARCTION
• UNSTABLE ANGINA
• HUMAN PLATELETS
• ASPIRIN
• CLOPIDOGREL
• PREVENTION
• VORAPAXAR
• CLONING

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 mu M) and 10h (PAR4 IC50 = 179 nM, PAR1 response IC50 > 30 mu M) maintained an overall favorable in vitro DMPK profile, encouraging rat/mouse in vivo pharmacokinetics (PK) and activity against gamma-thrombin.

• 出版日期2016-8-25
• 单位西北农林科技大学