Macrocyclic hexapeptide analogues of the thrombin receptor (PAR-1) activation motif SFLLRN

• Published in: Bioorganic & medicinal chemistry letters Vol. 9; no. 2; pp. 255 - 260
• Main Authors: McComsey, David F., Hecker, Leonard R., Andrade-Gordon, Patricia, Addo, Michael F., Maryanoff, Bruce E.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 18.01.1999; Elsevier
• Subjects: Biological and medical sciences; Blood Platelets - drug effects; Blood. Blood coagulation. Reticuloendothelial system; Inhibitory Concentration 50; Medical sciences; Pharmacology. Drug treatments; Receptor, PAR-1; Receptors, Thrombin - chemistry; Temperature; Thrombin - chemistry; Thrombin - drug effects; Agonist; Serine endopeptidases; Peptides; Phenylalanine; Enzyme; Cyclic peptides; Thrombin; Leucine; Glycine; In vitro; Hexapeptide; Macrocycle; Peptidases; Structure activity relation; Lysine; Asparagine; Hydrolases; Peptide synthesis; Solid phase; Chemical synthesis; Biological receptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(98)00731-8

The thrombin receptor (PAR-1) is activated by α-thrombin to stimulate various cell types, including platelets, through the tethered-ligand sequence SFLLRN. Macrocyclic peptide analogues of SFLLRN were synthesized and evaluated in vitro. In general, the compounds were much less potent in inducing platelet aggregation relative to SFLLRN-NH 2 and did not act as antagonists of α-thrombin. Derivative 3c was the most potent macrocycle in activating PAR-1, with an EC 50 of 24 μM. Macrocyclic peptide analogues of SFLLRN, the activation motif for the thrombin receptor (PAR-1), were synthesized and evaluated in vitro for their effects on PAR-1. The compounds were much less potent as agonists than SFLLRN-NH 2 and did not act as antagonists of α-thrombin. Derivative 3c, a cyclic analogue of GFKLFN-NH 2, was the most potent macrocycle in activating PAR-1; it had an EC 50 of 24 μM in inducing platelet aggregation.