Diarylsulfonamides as selective, non-peptidic thrombin inhibitors

Abstract Based on the structures of aminopyridine thrombin inhibitors ( 1 ), a series of aminoalkyl- and guanidinoalkyl-substituted diarylsulfonamides were prepared. The most potent derivative, N -[3-(4-guanidinobutoxy)-5-methyl-phenyl]-benzenesulfonamide ( 6c ) had Ki = 0.18 μM for thrombin and did not inhibit trypsin, plasmin, or factor Xa. Comparison of the X-ray structures of the thrombin/ 1b and the thrombin/ 6c complexes revealed important aspects which govern the binding of such diarylsulfonamides to thrombin.