DIBASIC BENZO[B]THIOPHENE DERIVATIVES AS A NOVEL CLASS OF ACTIVE-SITE-DIRECTED THROMBIN INHIBITORS - 2 - EXPLORING INTERACTIONS AT THE PROXIMAL (S-2) BINDING-SITE

In an effort to increase the thrombin inhibitory activity of a novel s eries of inhibitors (i.e., 1a), substituents were incorporated at the C-3'' position of the C-3 aryl ring (2). Consistent with the X-ray cry stallography studies, small hydrophobic groups at the C-3'' site (Br a nd Me) enhanced thrombin inhibitory activity by 8-fold. However, a few more hydrophilic substituents (NO2 and OMe) also enhanced the potency of the series. The biological results are discussed in terms of molec ular modeling studies. (C) 1998 Elsevier Science Ltd. All rights reser ved.