Abstract

Two synthetic libraries based on a core isoxazoline motif have been designed and prepared specifically to probe the S1 and S4 binding pockets of the Factor Xa enzyme active sites. A highly efficient parallel solution phase synthetic method resulted in the synthesis of 3-arylisoxazoline-5-carboxamides and 3-arylisoxazoline-5-acetamides libraries yielding 192 compounds in total. Highlights of this work include preparation of the isoxazoline cores via a [3+2] cycloaddition between oximes with acrylates or vinyl acetates and the use of activated p-nitrophenyl esters for ease of amide formation and reaction purification.

Keywords: Arylisoxazolines, Docking, Factor Xa, Glide, Library synthesis, Thromboembolic diseases, isoxazoline, nitrophenyl, acrylates, warfarin, hemostatic, Thromboembolic, SCAFFOLDS, stereocenters, caboxylates