Inhibition of cellular action of thrombin by N3-cyclopropyl-7-{[4-(1-methylethyl) phenyl] methyl}-7H-pyrrolo [3, 2-f] quinazoline-1, 3-diamine (SCH 79797), a nonpeptide …
HS Ahn, C Foster, G Boykow, A Stamford… - Biochemical …, 2000 - Elsevier
HS Ahn, C Foster, G Boykow, A Stamford, M Manna, M Graziano
Biochemical pharmacology, 2000•ElsevierA growing body of evidence suggests an important contribution of the cellular actions of
thrombin to thrombosis and restenosis following angioplasty. Recently we reported on SCH
79797 (N3-cyclopropyl-7-{[4-(1-methylethyl) phenyl] methyl}-7H-pyrrolo [3, 2-f] quinazoline-
1, 3-diamine) and its analogs as new potent, nonpeptide thrombin receptor antagonists. This
study further characterizes the biochemical and pharmacological actions of
pyrroloquinazoline inhibitors of protease activated receptor-1 (PAR-1) in human platelets …
thrombin to thrombosis and restenosis following angioplasty. Recently we reported on SCH
79797 (N3-cyclopropyl-7-{[4-(1-methylethyl) phenyl] methyl}-7H-pyrrolo [3, 2-f] quinazoline-
1, 3-diamine) and its analogs as new potent, nonpeptide thrombin receptor antagonists. This
study further characterizes the biochemical and pharmacological actions of
pyrroloquinazoline inhibitors of protease activated receptor-1 (PAR-1) in human platelets …
A growing body of evidence suggests an important contribution of the cellular actions of thrombin to thrombosis and restenosis following angioplasty. Recently we reported on SCH 79797 (N3-cyclopropyl-7-{[4-(1-methylethyl)phenyl]methyl}-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine) and its analogs as new potent, nonpeptide thrombin receptor antagonists. This study further characterizes the biochemical and pharmacological actions of pyrroloquinazoline inhibitors of protease activated receptor-1 (PAR-1) in human platelets and coronary artery smooth muscle cells (hCASMC). SCH 79797 and its N-methyl analog (SCH 203099) inhibited binding of a high-affinity thrombin receptor-activating peptide ([3H]haTRAP, Ala-Phe(p-F)-Arg-ChA-HArg-[3H]Tyr-NH2) to PAR-1 with ic50 values of 70 and 45 nM, respectively. SCH 79797 inhibited [3H]haTRAP binding in a competitive manner. SCH 79797 and SCH 203099 inhibited α-thrombin- and haTRAP-induced aggregation of human platelets, but did not inhibit human platelet aggregation induced by the tethered ligand agonist for protease-activated receptor-4 (PAR-4), γ-thrombin, ADP, or collagen. SCH 203099 inhibited surface expression of P-selectin induced by haTRAP and thrombin, and it did not increase P-selectin expression or prevent thrombin cleavage of the receptor. Thrombin and TFLLRNPNDK-NH2 (TK), a PAR-1-selective agonist, produced transient increases in cytosolic free Ca2+ concentration ([Ca2+]i) in hCASMC. This increase in [Ca2+]i was inhibited effectively by SCH 79797. However, the Ca2+ transients induced by SLIGKV-NH2, a PAR-2-selective agonist, were not inhibited by SCH 79797. Thrombin- and TK-stimulated [3H]thymidine incorporation also was inhibited completely by SCH 79797. The results of this study demonstrate that SCH 79797 and SCH 203099 are potent, selective antagonists of PAR-1 in human platelets and hCASMC. These data also suggest that the thrombin stimulation of Ca2+ transients and mitogenesis in hCASMC is mediated primarily through activation of PAR-1.
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