Exploratory solid-phase synthesis of factor Xa inhibitors: Discovery and application of P-3-heterocyclic amides as novel types of non-basic arginine surrogates

A series of novel FXa inhibitors 2a-m and 3a-f was discovered that feature heterocyclic carboxamides tethered to a d-diaminobutyric acid sidechain. Th ese neutral amide derivatives serve as novel P-3 d-arginine mimics. Pyrazin e carboxamide scaffolds afforded the most potent FXa inhibitors (e.g., 2b I C50 = 4.6 nM). The synthesis and biological activity of two focused librari es are reported. (C) 1999 Elsevier Science Ltd. All rights reserved.