General Solid-Phase Synthesis Approach To Prepare Mechanism-Based Aspartyl Protease Inhibitor Libraries. Identification of Potent Cathepsin D Inhibitors
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- 作者：Christina E. Lee ; Ellen K. Kick ; and Jonathan A. Ellman
- 刊名：Journal of the American Chemical Society
- 出版年：1998
- 出版时间：September 30, 1998
- 年：1998
- 卷：120
- 期：38
- 页码：9735 - 9747
- 全文大小：268K
- 年卷期：v.120,no.38(September 30, 1998)
- ISSN：1520-5126
文摘
A general method has been developed for the expedient solid-phase synthesis of aspartyl proteaseinhibitors that do not incorporate any amino acids. The synthesis approach was designed to allow theintroduction of diverse functionality at all four variable sites in inhibitors 1a,b using readily available precursors.Representative, analytically pure inhibitors were obtained in 45-64% overall yields for the 12-step solid-phase synthesis sequence that includes both stereoselective reduction and carbon-carbon bond forming steps.A library of 204 spatially separate compounds was also prepared and screened against cathepsin D and resultedin the identification of a number of potent small molecule inhibitors (Ki = 0.7-3 nM). The described synthesisapproach enables the rapid identification of small molecule inhibitors to diverse aspartyl protease targets.The general design principles are also applicable to other enzyme classes.