Preorganization of the hydroxyethylene dipeptide isostere: the preferred conformation in solution resembles the
Paloma Vidal1, David Timm, Howard Broughton
1Discovery Chemistry Research and Technologies, Lilly Research Laboratories, Centro de Investigación Lilly, Avenida de la Industria 30, 28108 Alcobendas, Madrid, Spain.
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.
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