Discovery and Structure−Activity Relationship of 3-Methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide (APD791): A Highly Selective 5-Hydroxytryptamine
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- 作者：Yifeng Xiong ; Bradley R. Teegarden ; Jin-Sun Karoline Choi ; Sonja Strah-Pleynet ; Marc Decaire ; Honnappa Jayakumar ; Peter I. Dosa ; Martin D. Casper ; Lan Pham ; Konrad Feichtinger ; Brett Ullman ; John Adam
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：June 10, 2010
- 年：2010
- 卷：53
- 期：11
- 页码：4412-4421
- 全文大小：868K
- 年卷期：v.53,no.11(June 10, 2010)
- ISSN：1520-4804
文摘
Serotonin, which is stored in platelets and is released during thrombosis, activates platelets via the 5-HT2A receptor. 5-HT2A receptor inverse agonists thus represent a potential new class of antithrombotic agents. Our medicinal program began with known compounds that displayed binding affinity for the recombinant 5-HT2A receptor, but which had poor activity when tested in human plasma platelet inhibition assays. We herein describe a series of phenyl pyrazole inverse agonists optimized for selectivity, aqueous solubility, antiplatelet activity, low hERG activity, and good pharmacokinetic properties, resulting in the discovery of 10k (APD791). 10k inhibited serotonin-amplified human platelet aggregation with an IC50 = 8.7 nM and had negligible binding affinity for the closely related 5-HT2B and 5-HT2C receptors. 10k was orally bioavailable in rats, dogs, and monkeys and had an acceptable safety profile. As a result, 10k was selected further evaluation and advanced into clinical development as a potential treatment for arterial thrombosis.