Vorapaxar discovery

The above narrative exemplifies a successful lead identification story, ensued by a successful lead optimization that led to the discovery of the FDA-approved drug vorapaxar. The original hit (2) was a racemic synthetic analog of himbacine, a natural product that has no thrombin receptor activity. Had we made this analog in the absolute chirality of himbacine, we would have missed the hit, since the thrombin receptor antagonist activity is exclusive to the unnatural e t-him-bacine series. The lead optimization efforts encountered several obstacles, as highlighted by the discontinuation of two recommended candidates. Within the project, we had to return several times to secondary lead generation and optimization in order to address the liabilities such as liver enzyme induction and sub-optimal mass balance that we encountered in the development candidates. 

Chackalamannil, S. (2011) The discovery of vorapaxar (SCH 530348), a thrombin receptor (protease activated receptor-1) antagonist with potent antiplatelet effects, in Accounts in Drug Discovery Case Studies in Medicinal Chemistry, RSC Drug Discovery Series No. 4 (eds J.C. Barrish, P. H. Carter, P.T.W. Cheng, and R. Zahler), Royal Society of Chemistry, Cambridge, UK, pp. 25-49. 

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