SSR182289A, a selective and potent orally active thrombin inhibitor
SSR182289A, a selective and potent orally active thrombin inhibitor
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DOI：
10.1016/j.bmc.2004.01.016
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发表时间：
2004-04-01
影响因子：
3.5
通讯作者：
Herbert, JM
中科院分区：
文献类型：
--
作者：
Altenburger, JM;Lassalle, GY;Herbert, JM
SSR182289A 1是合理优化过程的结果，导致口服活性凝血酶抑制剂。该结构包含一个原始的2-(乙酰氨基)-[1，1‘-联苯]-3-磺酰基N-末端基序，中心的L-Arg替代物携带弱碱性的3-氨基吡啶，以及C-末端的罕见的4-二氟哌啶。它的合成是收敛的，钯催化用于构建关键的C-C键：双芳基片段的Suzuki偶联和中心氨基酸链的Delta-epsilon键的Sonogashira反应。该化合物是一种有效的凝血酶活性的体外抑制剂，并在三种血栓形成的大鼠模型中显示出强大的口服抗血栓形成能力。通过检测SSR182289A 1-凝血酶晶体结构中的相互作用，可以合理地解释体外观察到的效力。因此，选择了SSR182289A 1进行进一步开发。(C)2004爱思唯尔有限公司。保留所有权利。
SSR182289A 1 is the result of a rational optimisation process leading to an orally active thrombin inhibitor. The structure incorporates an original 2-(acetylamino)-[1,1'-biphenyl]-3-sulfonyl N-terminal motif, a central L-Arg surrogate carrying a weakly basic 3-amino-pyridine, and an unusual 4-difluoropiperidine at the C-terminus. Its synthesis is convergent and palladium catalysis has been employed for the construction of the key C-C bonds: Suzuki coupling for the bis-aryl fragment and Sonogashira reaction for the delta-epsilon bond of the central amino-acid chain. The compound is a potent inhibitor of thrombin's activities in vitro and demonstrates potent oral anti-thrombotic potencies in three rat models of thrombosis. The observed in vitro potency could be rationalized through the examination of the interactions within the SSR182289A 1 - thrombin crystal structure. SSR182289A 1, has been therefore selected for further development. (C) 2004 Elsevier Ltd. All rights reserved.