title: 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.
authors.affiliation: Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, California 92121, USA. yxiong@arenapharm.com
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Xiong
authors.forename: Bradley R
authors.initials: BR
authors.lastname: Teegarden
authors.forename: Jin-Sun Karoline
authors.initials: JS
authors.lastname: Choi
authors.forename: Sonja
authors.initials: S
authors.lastname: Strah-Pleynet
authors.forename: Marc
authors.initials: M
authors.lastname: Decaire
authors.forename: Honnappa
authors.initials: H
authors.lastname: Jayakumar
authors.forename: Peter I
authors.initials: PI
authors.lastname: Dosa
authors.forename: Martin D
authors.initials: MD
authors.lastname: Casper
authors.forename: Lan
authors.initials: L
authors.lastname: Pham
authors.forename: Konrad
authors.initials: K
authors.lastname: Feichtinger
authors.forename: Brett
authors.initials: B
authors.lastname: Ullman
authors.forename: John
authors.initials: J
authors.lastname: Adams
authors.forename: Diane
authors.initials: D
authors.lastname: Yuskin
authors.forename: John
authors.initials: J
authors.lastname: Frazer
authors.forename: Michael
authors.initials: M
authors.lastname: Morgan
authors.forename: Abu
authors.initials: A
authors.lastname: Sadeque
authors.forename: Weichao
authors.initials: W
authors.lastname: Chen
authors.forename: Robert R
authors.initials: RR
authors.lastname: Webb
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Connolly
authors.forename: Graeme
authors.initials: G
authors.lastname: Semple
authors.forename: Hussien
authors.initials: H
authors.lastname: Al-Shamma
mesh_terms: D000818:Animals; D001158:Arteries / Q000187:drug effects*; D001549:Benzamides / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D055808:Drug Discovery / Q000379:methods*; D054314:Drug Inverse Agonism; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D009025:Morpholines / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D011720:Pyrazoles / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013927:Thrombosis / Q000188:drug therapy* / Q000378:metabolism
chemical_list: C544126:APD791; D001549:Benzamides; D009025:Morpholines; D011720:Pyrazoles; D044402:Receptor, Serotonin, 5-HT2A; D058826:Serotonin 5-HT2 Receptor Agonists