Substrate Related O,O-Dialkyldipeptidylaminophosphonates, A New Type of Thrombin Inhibitor
Substrate Related O,O-Dialkyldipeptidylaminophosphonates, A New Type of Thrombin Inhibitor
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底物相关的 O,O-二烷基二肽氨基膦酸盐，一种新型凝血酶抑制剂
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发表时间：
1996
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通讯作者：
J. Deadman
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作者：
D. Green;G. Patel;S. Elgendy;J. Baban;E. Skordalakes;W. Husman;C. Goodwin;M. Scully;V. Kakkar;J. Deadman
用LiBH_4/Me_3SiCl在THF中于室温下还原O，O-二烷基1-羟基亚氨基烷膦酸酯前体，可方便地得到O，O-二烷基1-氨基烷膦酸酯，产率高，纯度高。O，O-二烷基1-氨基苄基膦酸酯可以由其1-苄基氨基苄基膦酸酯前体的催化氢解以高产率和高纯度制备。这些生物活性氨基膦酸酯，当偶联到底物衍生的二肽时，产生一系列基于“纤维蛋白原样”序列H-D-Phe-Pro-Arg的新型膦酰三肽;其中磷结构单元取代“P1”Arg。这些三肽对胰蛋白酶样丝氨酸蛋白酶凝血酶（一种在心血管系统中起关键作用的普遍存在的酶）显示出显著的抑制特异性。所述化合物对凝血酶具有在微摩尔范围内的体外初始Ki。化合物Z-D-Dpa-Pro-PglP（OiPr）2的进一步酶动力学分析（IC 50 11.7微摩尔/升）
Abstract The facile reduction of O,O-dialkyl 1-hydroxyiminoalkanephosphonate precursors, using LiBH4/Me3SiCl in THF at ambient temperature, conveniently affords O,O-dialkyl 1-aminoalkanephosphonates in good yield and high state of purity. O,O-Dialkyl 1-aminobenzylphosphonates may be prepared in high yield and purity from catalytic hydrogenolysis of their 1-benzylaminobenzylphosphonate precursors. These biologically active aminophosphonates, when coupled to substrate derived dipeptides, produced a range of novel phosphonotripeptides based upon the ‘fibrinogen-like’ sequence H-D-Phe-Pro-Arg; where the phosphorus structural units replace the ‘Pl’Arg. These tripeptides showed a marked inhibitory specificity towards the trypsin-like serine protease thrombin, a ubiquitous enzyme that plays a crucial role in the cardiovascular system. The compounds possess an initial Ki in-vitro in the micromolar range against thrombin. Further enzyme kinetic analysis of the compound Z-D-Dpa-Pro-PglP(OiPr)2 (IC50 11.7 micromolar...