Vorapaxar

P450 2J2 has also been found to be rather proficient in the oxidation of a number of drags, including terfenadine [1129, 1148], ebastine [1149], astemizole [1150, 1151], hydroxyebas-tine and carebastine [1152], eperisone [1153], vorapaxar [1154], amiodarone [1155], albendazole and fenbendazole [833], thioridazine, me-... 

Ghosal A, Lu X, Penner N, Gao L, Ramanathan R, Chowdhury SK, Kishnani NS, Alton KB (2011) Identification of human liver cytochrome P450 enzymes involved in the metabolism of SCH 530348 (Vorapaxar), a potent oral thrombin protease-activated receptor 1 antagonist. Drug Metab Dispos 39 30-38... 

Thrombin receptor (PAR-1) antagonists Vorapaxar Zontivity Oral Launched... 

A high-resolution crystal structure of vorapaxar-bound to PAR-1 has been recently published [22]. The structure reveals that the vorapaxar binding pocket. 

Vorapaxar From Lead Identification to FI3A Approval... 

In additional functional assays, vorapaxar inhibited thrombin-induced calcium transient in human coronary artery smooth muscle cells (HCASMC) with a A) of... 

Table 19.5 Summary of in vitro and pharmacokinetic data for vorapaxar (2).

In phase I clinical studies, vorapaxar (SCH 530348) demonstrated excellent safety and tolerability. In pharmacodynamic platelet aggregation studies, the compound showed a robust >90% inhibition of platelet aggregation at all tested doses for a sustained period of time [38]. The target level of platelet aggregation throughout the 28-day treatment period was maintained by a 2.5 mg once-daily maintenance dose. 

Analysis of the TRACER study data revealed that among a subgroup of patients who were taking vorapaxar plus aspirin, but not a P2Yi2 antagonist at randomization, the risk of bleeding was not increased, and the observed effect on efficacy tended to be more pronounced [44]. This initial finding seems to have been corroborated by a more favorable clinical outcome observed in the TRA 2 P-TIMI 50 study as described below. 

Among patients without a history of stroke, the addition of vorapaxar reduced the risk of CV death, heart attack, stroke, or urgent coronary revascularization by 14% compared to placebo plus standard of care (10.6% versus 11.8%,... 

Results of TRA 2 P-TIMI 50 trial demonstrated for the first time that a thrombin receptor (PAR-1) antagonist, when added to standard antiplatelet therapy that comprises P2Yi2 antagonist and aspirin, reduced the risk of recurrent cardiovascular events in the long-term. Vorapaxar received FDA approval in 2014 to reduce the risk of myocardial infarction, stroke, cardiovascular death, and revascularization procedures in patients who have had a heart attack or who have peripheral arterial disease. 

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. 

The authors acknowledge Dr. William J. Greenlee, Dr. Madhu Chintala and the rest of the thrombin receptor antagonist team at Schering-Plow that was responsible for the development of vorapaxar. Several of their individual contributions are cited in the reference section. 

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. 

Tricoci, P., Huang, Z., Held, C., Molitemo, D.J. et al and the TRACER Investigators (2012) Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. New England Journal of Medicine, 366, 20-33. 

Morrow, DA., Braunwald, E., Bonaca, M.P., Ameriso, A.F. et al and the TRA 2P-TIMI 50 Steering Committee and Investigators (2012) Vorapaxar in the secondary prevention of atherothrombotic events. New England Journal of Medicine, 366,1404-1413. 

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