The discovery of APD791 demonstrates a highly selective, orally bioavailable 5-HT2A receptor inverse agonist with potent antiplatelet activity, supporting its advancement into clinical development for arterial thrombosis.
APD791 warrants first-in-human testing; leaves open its efficacy and safety in 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.
No takes yet. Share an insight, caveat, or question.
Xiong et al. (2010) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: