title: Thrombin receptor (PAR-1) antagonists. Heterocycle-based peptidomimetics of the SFLLR agonist motif.
abstract: The thrombin receptor (PAR-1) is activated by alpha-thrombin to stimulate various cell types, including platelets, through the tethered-ligand sequence SFLLRN. A series of azole-based carboxamides, designed after SFLLR, were synthesized and evaluated in vitro. The compounds inhibited platelet aggregation induced by SFLLRN-NH2 or alpha-thrombin, and blocked the binding of [3H]-S-(p-F-Phe)-Har-L-Har-KY-NH2 to a CHRF membrane preparation of PAR-1. Oxazole 30 bound to PAR-1 with an IC50 of 1.6 microM, and gave IC50 values of 25 microM and 6.6 microM against alpha-thrombin- and SFLLRN-NH2-induced platelet aggregation, respectively.
authors.affiliation: R. W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Hoekstra
authors.forename: B L
authors.initials: BL
authors.lastname: Hulshizer
authors.forename: D F
authors.initials: DF
authors.lastname: McComsey
authors.forename: P
authors.initials: P
authors.lastname: Andrade-Gordon
authors.forename: J A
authors.initials: JA
authors.lastname: Kauffman
authors.forename: M F
authors.initials: MF
authors.lastname: Addo
authors.forename: D
authors.initials: D
authors.lastname: Oksenberg
authors.forename: R M
authors.initials: RM
authors.lastname: Scarborough
authors.forename: B E
authors.initials: BE
authors.lastname: Maryanoff
mesh_terms: D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018716:Molecular Mimicry; D010446:Peptide Fragments / Q000737:chemistry*; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D006571:Heterocyclic Compounds; D010446:Peptide Fragments; D010975:Platelet Aggregation Inhibitors; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; C082835:thrombin receptor peptide (42-47)