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
Letters in Drug Design & Discovery
Title: Design and Synthesis of 3-Arylisoxazoline-5-Carboxamide and 3-Arylisoxazoline-5-Acetamide Libraries as Potential Factor Xa Inhibitors
Volume: 9 Issue: 1
Author(s): John F. Quinn, Brian T. Gregg, Douglas B. Kitchen, Robert M. Lewis, Dana A. Razzano, Lauren E. Kayser, Levon J. Schilling and Kathryn C. Golden
Affiliation:
Keywords: Arylisoxazolines, Docking, Factor Xa, Glide, Library synthesis, Thromboembolic diseases, isoxazoline, nitrophenyl, acrylates, warfarin, hemostatic, Thromboembolic, SCAFFOLDS, stereocenters, caboxylates
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.
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Cite this article as:
F. Quinn John, T. Gregg Brian, B. Kitchen Douglas, M. Lewis Robert, A. Razzano Dana, E. Kayser Lauren, J. Schilling Levon and C. Golden Kathryn, Design and Synthesis of 3-Arylisoxazoline-5-Carboxamide and 3-Arylisoxazoline-5-Acetamide Libraries as Potential Factor Xa Inhibitors, Letters in Drug Design & Discovery 2012; 9 (1) . https://dx.doi.org/10.2174/157018012798193035
DOI https://dx.doi.org/10.2174/157018012798193035 |
Print ISSN 1570-1808 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-628X |
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