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-hydroxytryptamine2A receptor inverse agonist for the treatment of arterial thrombosis

  • J Med Chem. 2010 Jun 10;53(11):4412-21. doi: 10.1021/jm100044a.
Yifeng Xiong  1 ,  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 Adams ,  Diane Yuskin ,  John Frazer ,  Michael Morgan ,  Abu Sadeque ,  Weichao Chen ,  Robert R Webb ,  Daniel T Connolly ,  Graeme Semple ,  Hussien Al-Shamma
Affiliations
  • 1. Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, California 92121, USA. [email protected]
PMID: 20455563 DOI: 10.1021/jm100044a
Abstract

Serotonin, which is stored in platelets and is released during thrombosis, activates platelets via the 5-HT(2A) receptor. 5-HT(2A) 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-HT(2A) 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 IC(50) = 8.7 nM and had negligible binding affinity for the closely related 5-HT(2B) and 5-HT(2C) 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.

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