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Preorganization of the hydroxyethylene dipeptide isostere: the preferred conformation in solution resembles the conformation bound to BACE.

作者信息

Vidal Paloma, Timm David, Broughton Howard, Chen Shu-Hui, Martín José A, Rivera-Sagredo Alfonso, McCarthy James R, Shapiro Michael J, Espinosa Juan F

机构信息

Discovery Chemistry Research and Technologies, Lilly Research Laboratories, Centro de Investigación Lilly, Avenida de la Industria 30, 28108 Alcobendas, Madrid, Spain.

出版信息

J Med Chem. 2005 Dec 1;48(24):7623-7. doi: 10.1021/jm050631+.

DOI:10.1021/jm050631+
PMID:16302802
Abstract

Conformational analysis in solution of beta-secretase inhibitors 1 and 2 by NMR spectroscopy reveals that the hydroxyethylene isostere, an apparently flexible fragment widely used as a scissile bond replacement in aspartic protease inhibitors, exists in one predominant conformation in solution. This preferred conformation is similar to that adopted by the hydroxyethylene core of 1 in complex with beta-secretase and that adopted by hydroxyethylene cores of related compounds when bound to aspartic proteases, indicating that this structural unit is preorganized in solution.

摘要

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