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 thrombin receptor antagonist
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 thrombin receptor antagonist
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DOI：
10.1016/s0006-2952(00)00460-3
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发表时间：
2000-11-15
影响因子：
5.8
通讯作者：
Graziano, M
中科院分区：
文献类型：
--
作者：
Ahn, HS;Foster, C;Graziano, M
越来越多的证据表明凝血酶的细胞作用对血管成形术后血栓形成和再狭窄有重要作用。最近，我们报道了SCH 79797（N3-环丙基-7-{[4-（1-甲基乙基）苯基]及其类似物作为新的强效非肽类凝血酶受体拮抗剂。本研究进一步表征了吡咯并喹唑啉蛋白酶激活受体-1（PAR-1）抑制剂在人血小板和冠状动脉平滑肌细胞（hCASMC）中的生化和药理作用。SCH 79797及其N-甲基类似物（SCH 203099）抑制高亲和力凝血酶受体激活肽（[H-3]haTRAP，Ala-Phe（p-F）-Arg-ChA-HArg-[H-3]Tyr-NK）与PAR-1的结合，IC 50值分别为70和45 nM。SCH 79797以竞争性方式抑制[H-3]haTRAP结合。SCH 79797和SCH 203099可抑制α-凝血酶和haTRAP诱导的人血小板聚集，但不能抑制蛋白酶激活受体-4（PAR-4）、γ-凝血酶、ADP或胶原蛋白的束缚配体激动剂诱导的人血小板聚集。SCH 203099抑制由haTRAP和凝血酶诱导的P-选择素的表面表达，并且其不增加P-选择素表达或阻止受体的凝血酶裂解。凝血酶和TFLLRNPNDK-NH 2（TK）（PAR-1选择性激动剂）在hCASMC中产生胞质游离Ca 2+浓度（[Ca 2 +]（i））的瞬时增加。SCH 79797可有效抑制[Ca 2 +]（i）的增加。然而，SCH 79797不抑制PAR-2选择性激动剂SLIGKV-NH 2诱导的Ca 2+瞬变。SCH 79797也完全抑制凝血酶和TK刺激的[H-3]胸苷掺入。本研究结果表明，SCH 79797和SCH 203099是人血小板和hCASMC中PAR-1的强效选择性拮抗剂。这些数据还表明，凝血酶刺激的钙瞬变和有丝分裂hCASMC主要是通过激活PAR-1介导的。(C)2000 Elsevier Science Inc.
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] 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 ([H-3]haTRAP, Ala-Phe(p-F)-Arg-ChA-HArg-[H-3]Tyr-NK,) to PAR-1 with IC50 values of 70 and 45 nM, respectively. SCH 79797 inhibited [H-3]haTRAP binding in a competitive manner. SCH 79797 and SCH 203099 inhibited alpha-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), gamma-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-l 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 [H-3]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. (C) 2000 Elsevier Science Inc.