Discovery and structure-activity relationship of 3-methoxy-N-(3-(1-methyl-1 H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide (APD791): A highly selective 5-hydroxytryptamine_2A 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 IC₅₀ = 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.