Design and Synthesis of 3-Arylisoxazoline-5-Carboxamide and 3-Arylisoxazoline-5-Acetamide Libraries as Potential Factor Xa Inhibitors
John F. Quinn,
Brian T. Gregg,
Douglas B. Kitchen,
Robert M. Lewis,
Dana A. Razzano,
Lauren E. Kayser,
Levon J. Schilling,
Kathryn C. Golden.
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
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