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.
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.
Xiong
Yifeng
Y
Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, California 92121, USA. yxiong@arenapharm.com
Teegarden
Bradley R
BR
Choi
Jin-Sun Karoline
JS
Strah-Pleynet
Sonja
S
Decaire
Marc
M
Jayakumar
Honnappa
H
Dosa
Peter I
PI
Casper
Martin D
MD
Pham
Lan
L
Feichtinger
Konrad
K
Ullman
Brett
B
Adams
John
J
Yuskin
Diane
D
Frazer
John
J
Morgan
Michael
M
Sadeque
Abu
A
Chen
Weichao
W
Webb
Robert R
RR
Connolly
Daniel T
DT
Semple
Graeme
G
Al-Shamma
Hussien
H
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
C544126:APD791; D001549:Benzamides; D009025:Morpholines; D011720:Pyrazoles; D044402:Receptor, Serotonin, 5-HT2A; D058826:Serotonin 5-HT2 Receptor Agonists