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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.

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.
AuthorsYifeng 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 Adams, Diane Yuskin, John Frazer, Michael Morgan, Abu Sadeque, Weichao Chen, Robert R Webb, Daniel T Connolly, Graeme Semple, Hussien Al-Shamma
JournalJournal of medicinal chemistry (J Med Chem) Vol. 53 Issue 11 Pg. 4412-21 (Jun 10 2010) ISSN: 1520-4804 [Electronic] United States
PMID20455563 (Publication Type: Journal Article)
Chemical References
  • APD791
  • Benzamides
  • Morpholines
  • Pyrazoles
  • Receptor, Serotonin, 5-HT2A
  • Serotonin 5-HT2 Receptor Agonists
Topics
  • Animals
  • Arteries (drug effects)
  • Benzamides (chemistry, metabolism, pharmacokinetics, pharmacology)
  • Dogs
  • Drug Discovery (methods)
  • Drug Inverse Agonism
  • Female
  • Humans
  • Inhibitory Concentration 50
  • Male
  • Morpholines (chemistry, metabolism, pharmacokinetics, pharmacology)
  • Platelet Aggregation (drug effects)
  • Pyrazoles (chemistry, metabolism, pharmacokinetics, pharmacology)
  • Rats
  • Receptor, Serotonin, 5-HT2A (metabolism)
  • Serotonin 5-HT2 Receptor Agonists
  • Structure-Activity Relationship
  • Substrate Specificity
  • Thrombosis (drug therapy, metabolism)

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