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Aminoethylenes:  A Tetrahedral Intermediate Isostere Yielding Potent Inhibitors of the Aspartyl Protease BACE-1

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journal contribution
posted on 09.02.2006, 00:00 by Wenjin Yang, Wanli Lu, Yafan Lu, Min Zhong, Jian Sun, Anila E. Thomas, Jennifer M. Wilkinson, Raymond V. Fucini, Melissa Lam, Mike Randal, Xiao-Ping Shi, Jeffrey W. Jacobs, Robert S. McDowell, Eric M. Gordon, Marcus D. Ballinger
A series of novel β-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing an aminoethylene (AE) tetrahedral intermediate isostere were synthesized and evaluated in comparison to corresponding hydroxyethylene (HE) compounds. Enzymatic inhibitory values were similar for both isosteres, as were structure−activity relationships with respect to stereochemical preference and substituent variation (P2/P3, P1, and P2‘); however, the AE compounds were markedly more potent in a cell-based assay for reduction of beta-secretase activity. The incorporation of preferred P2/P3, P1, and P2‘ substituents into the AE pharmacophore yielded compound 7, which possessed enzymatic and cell assay IC50s of 26 nM and 180 nM, respectively. A three-dimensional crystal structure of 7 in complex with BACE-1 revealed that the amino group of the inhibitor core engages the catalytic aspartates in a manner analogous to hydroxyl groups in HE inhibitors. The AE isostere class represents a promising advance in the development of BACE-1 inhibitors.

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