Design, syntheses, and activity of new 3-[(sulfonylaryl)-amino]-1,4-benzodiazepin-2-one derivatives as α-thrombin inhibitors

Article abstract of DOI:10.1016/S0223-5234(98)80048-2

Thrombin plays a central role in thrombosis. Because of the medical need for novel antithrombotic drugs, a search for structurally novel thrombin inhibitors was undertaken. in the absence of a crystal structure, a class was designed based on a modeling approach which involved placing the essential functional groups of the thrombin antagonist MD-805 [1] (Argatroban) into the benzodiazepine nucleus. The best superposition was obtained with a 1,4-benzodiazepin-2-one containing a 1,2,3,3-tetrahydro quinalylsulfonyl moiety in the 3-position, a guanidino-phenyl at the 5-position, and N¹-substituted with an acetic acid. Synthesis of these molecules provided compounds with an inhibitory activity with K(i) in the range of 40-1000 μM. A report on the crystal structure of thrombin*hirudin(55-65)*MD-805 complex [2] suggested subsequent molecular modeling investigations to rationalize the pharmacological results.