Heterocycle-peptide hybrid compounds. Aminotriazole-containing agonists of the thrombin receptor (PAR-1)

The thrombin receptor PAR-1 is activated by α-thrombin to stimulate cells, including platelets, through the tethered-ligand sequence SFLLRN. We have discovered a novel series of heterocycle-peptide hybrids comprised of a tripeptide segment, such as Cha-Arg-Phe, and an N-terminal heterocyclic group, many of which behave as full PAR-1 agonists. Certain compounds with an aminotriazole group, such as 4 and 16, are nearly as potent as SFLLRN-NH2 in inducing platelet aggregation. Also, some arylethenoyl “N-capped” compounds, such as 52 and 57, exhibit mixed PAR-1 agonist-antagonist activity.