Thrombin receptor activation

Tagging and recovery of associated proteins, as in RNA-TRAP also thrombin receptor activation peptide Thyroid hormone response elements Thyrotropin-releasing hormone... 

Goodwin CA, Wheder-Jbnes CPD, Kakkar W, Deadman JJ, Authi KS, Scully MF Thrombin receptor activating peptide does not stimulate platdd procoagulant activity. Biochem Biophys Res Common 202 321,1994... 

Lasne D, Donato J, Fdd H, Rendu F Different abilities of thrombin receptor activating peptide and thrombin to induce platdd caldum rise and full rdease reaction. Thromb Haemost 74 1323,1995... 

AND RJA, TXjrNELL as, QiabHAM PW. Cdlular consequences of thrombin-receptor activation. Biochem J313 353-368,1996. 

Grabham, P. and Cunningham, D. B., Thrombin receptor activation stimulates astrocyte proliferation and reversal of stellatation by distinct pathways. Involvement of tyrosine phosphorylation, / Neurochem., 64, 583, 1995. 

Structure-activity studies with thrombin receptor-activating peptides (TRAPs). 

TRAP, thrombin receptor-activating peptide PI4, SFLLRNPNDKYEPF P7, SFLLRNP P7-NH2, SFLLRI -NH2 P5, SFLLR PS-NHz, SFLLR-NH2 P5VR-NH2, SFLVR-NHj Cha, cyclohexylalanyl Mpr, mercaptopropionyl LM, gastric longitudinal muscle. 

Figure 19.2 The tethered ligand mechanism of thrombin receptor activation. Thrombin binds to the extracellular domain of the receptor and cleaves it at Arg -Ser. The newly generated serine N-terminus binds intramolecularly to the receptor, triggering cellular activation.

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. 

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