Thrombin receptor antagonists

Himbacine (80) Alkaloid SCH 530348 (TRA) (81) Cardiovascular diseases (antiplatelet agent) Thrombin receptor antagonist Phase III (acute coronary syndromes) Schering-Plough 623-626... 

Clasby MC, Chackalamannil S, Czamiecki M, Doller D, Eagen K, Greenlee W, Kao G Lin Y, Tsai H, Xia Y, Ahn HS, Agans-Fantuzzi J, Boykow G Chintala M, Foster C, Smith-Torhan A, Alton K, Bryant M, Hsieh Y, Fan J, Palamanda J. (2007) Metabolism-based identification of a potent thrombin receptor antagonist. J Med Chem 50 129-138. 

Aplysillin A (527), with unknown double bond geometries was isolated from Aplysina fistularis and is a weak thrombin receptor antagonist [442]. 

PAR-1, results in the formation of platelet aggregation causing thrombotic disorders such as myocardial infarction, stroke, angina, and atherosclerosis. Benzimidazolone peptidomimetic derivatives effective as thrombin receptor antagonists have been prepared to address this disorder. 

In our own work, we wished to evaluate the actions of the putative thrombin receptor antagonist, Mpr-P10-NH2 in the rat gastric longitudinal muscle contraction assay and we wished to assess the actions of VR-NH2 both in the gastric contractile assay and in the platelet aggregation assay. As indicated by the data in Figure 7, Mpr-P10-NH2 which was an... 

Preclinical Data Supporting the Antiplatelet Effect of Thrombin Receptor Antagonists 1551... 

Lead Generation from Himbadne-derived Thrombin Receptor Antagonist Hit... 

Himbacine-derived Thrombin Receptor Antagonists s61 19.6.2.4 Generation of Aryl Himbacine Leads... 

From this structure-activity relationship study, the ethyl urethane 55 was identified as a promising thrombin receptor antagonist (Table 19.4). This compound showed a PAR-1 affinity of 4.7 nM in the binding assay. In the ex vivo platelet aggregation inhibition assay, 55 was quite potent, completely inhibiting... 

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., Wang, Y., Greenlee, W.J., Hu, Z., Xia, Y., Ahn, H.-S., Boykow, G., Hsieh, Y., Palamanda, J., Agans-Fantuzzi, J., Kurowski, S., Graziano, M., and Chintala, M. (2008) Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity. Journal of Medicinal Chemistry, 51 (11), 3061-3064. 

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