Diarylsulfonamides as selective, non-peptidic thrombin inhibitors

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 mu M 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. (C) 1998 Elsevier Science Ltd. All rights reserved.