A case history in natural product-based drug discovery: discovery of vorapaxar (Zontivity™)

Vorapaxar (Zontivity™) is an FDA approved antiplatelet agent that blocks platelet activation via protease activated receptor-1 (PAR-1), also known as thrombin receptor. The original PAR-1 lead was a racemic synthetic analog of the natural product (+)- himbacine. It was established early on that ent -himbacine absolute chirality was required for PAR-1 antagonism. The lead optimization efforts encountered several challenges, including synthesis of thousands of complex tricyclic himbacine analogs, discontinuation of multiple development candidates due to toxicological issues, need for non-human primate animal models, etc. Vorapaxar had a PAR-1 Ki of 8.1 nM and it showed potent ex-vivo platelet aggregation inhibition for >24 h in a cynomolgus monkey model after oral dosing at 0.1 mg/kg. Based on the successful clinical outcome, vorapaxar received FDA approval for the prevention of thrombotic cardiovascular events in patients with a history of myocardial infarction or peripheral arterial disease. Graphical abstract