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

摘要

A series of novel beta-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.En-zymatic inhibitory values were similar for both isosteres,as were structure-activity relationships with respect to stereochemical preference and substituent variation(P2/0P3,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 IC_(50)S 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.