Altenburger Jean-Michel, Lassalle Gilbert Y, Matrougui Mostapha, Galtier Daniel, Jetha Jean-Claude, Bocskei Zsolt, Berry Christopher N, Lunven Catherine, Lorrain Janine, Herault Jean-Pascal, Schaeffer Paul, O'Connor Stephen E, Herbert Jean-Marc
Sanofi-Synthélabo Research, Cardiovascular-Thrombosis Department, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin, Cedex, France.
Bioorg Med Chem. 2004 Apr 1;12(7):1713-30. doi: 10.1016/j.bmc.2004.01.016.
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- 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.
SSR182289A 1是合理优化过程的产物，最终得到一种口服活性凝血酶抑制剂。其结构包含一个独特的2-(乙酰氨基)-[1,1'-联苯]-3-磺酰基N端基序、一个带有弱碱性3-氨基吡啶的中心L-精氨酸替代物以及一个位于C端的不寻常的4-二氟哌啶。其合成是汇聚式的，钯催化用于构建关键的碳-碳键：双芳基片段采用铃木偶联反应，中心氨基酸链的δ键采用 Sonogashira 反应。该化合物在体外是凝血酶活性的有效抑制剂，并且在三种大鼠血栓形成模型中显示出强大的口服抗血栓效力。通过研究SSR182289A 1与凝血酶晶体结构中的相互作用，可以解释所观察到的体外效力。因此，SSR182289A 1已被选作进一步研发。
