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

…, OE Levy, TS Gibson, K Nguyen, JE Semple

Index: Ho, Jonathan Z.; Levy, Odile E.; Gibson, Tony S.; Nguyen, Khanh; Semple, J. Edward Bioorganic and Medicinal Chemistry Letters, 1999 , vol. 9, # 24 p. 3459 - 3464

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Citation Number: 7

Abstract

A series of novel FXa inhibitors 2a-m and 3a-f was discovered that feature heterocyclic carboxamides tethered to a d-diaminobutyric acid sidechain. These neutral amide derivatives serve as novel P3d-arginine mimics. Pyrazine carboxamide scaffolds afforded the most potent FXa inhibitors (eg, 2b IC50= 4.6 nM). The synthesis and biological activity of two focused libraries are reported.