三肽基氟代烷凝血酶抑制剂的合成与比较

Synthesis and comparison of tripeptidylfluoroalkane thrombin inhibitors.

作者信息

Neises B, Broersma R J, Tarnus C, Piriou F, Remy J M, Lintz C, Heminger E F, Kutcher L W

机构信息

Marion Merrell Dow Research Institute, Strasbourg, France.

出版信息

Bioorg Med Chem. 1995 Aug;3(8):1049-61. doi: 10.1016/0968-0896(95)00097-z.

DOI:10.1016/0968-0896(95)00097-z

PMID:7582979

Abstract

Fluorinated ketone thrombin inhibitors based on the peptide sequence methyl-(D)-Phe-Pro-Arg-CF2R were synthesized: MDL 73,446 (1, R = F); MDL 73,775 (2, R = CF3); and MDL 75,579 (3, R = CH2CH2CH3). These were shown to be highly effective, slow binding inhibitors of thrombin. Anticoagulant activity was dose-dependent with 3 > 2 > 1 at doubling thrombin time and APTT, respectively. Anticoagulant activity corresponded with efficacy in a platelet-dependent (FeCl3-induced) rat carotid artery thrombosis model. Arterial occlusion was dose-dependently prolonged with 3 > 2 > 1 at doubling the occlusion time.

摘要

基于肽序列甲基-(D)-苯丙氨酸-脯氨酸-精氨酸-CF₂R合成了氟化酮凝血酶抑制剂：MDL 73,446（1，R = F）；MDL 73,775（2，R = CF₃）；以及MDL 75,579（3，R = CH₂CH₂CH₃）。这些被证明是凝血酶的高效、慢结合抑制剂。抗凝活性呈剂量依赖性，在使凝血酶时间和活化部分凝血活酶时间加倍时，抗凝活性顺序为3 > 2 > 1。在血小板依赖性（FeCl₃诱导）大鼠颈动脉血栓形成模型中，抗凝活性与疗效相对应。在使闭塞时间加倍时，动脉闭塞时间呈剂量依赖性延长，顺序为3 > 2 > 1。