Highly Selective and Potent Human ?-Secretase?2 (BACE2) Inhibitors against Type?2 Diabetes: Design, Synthesis, X-ray Structure and Structure-Activity Relationship Studies.

ABSTRACT: Herein we present the design, synthesis, and biological evaluation of potent and highly selective ?-secretase?2 (memapsin?1, beta-site amyloid precursor protein cleaving enzyme?2, or BACE 2) inhibitors. BACE2 has been recognized as an exciting new target for type?2 diabetes. The X-ray structure of BACE1 bound to inhibitor 2?a {N3 -[(1S,2R)-1-benzyl-2-hydroxy-3-[[(1S,2S)-2-hydroxy-1-(isobutylcarbamoyl)propyl]amino]propyl]-5-[methyl(methylsulfonyl)amino]-N1 -[(1R)-1-phenylpropyl]benzene-1,3-dicarboxamide} containing a hydroxyethylamine isostere was determined. Based on this structure, a computational docking study was performed which led to inhibitor 2?a-bound BACE2 models. These were used to optimize the potency and selectivity of inhibitors. A systematic structure-activity relationship study led to the identification of determinants of the inhibitors' potency and selectivity toward the BACE2 enzyme. Inhibitors 2?d [N3 -[(1S,2R)-1-benzyl-2-hydroxy-3-[[(1S,2S)-2-hydroxy-1-(isobutylcarbamoyl)pentyl]amino]propyl]-N1 -methyl-N1 -[(1R)-1-phenylpropyl]benzene-1,3-dicarboxamide; Ki =0.031?nm, selectivity over BACE1: ?174?000-fold] and 3?l [N1 -((2S,3R)-3-hydroxy-1-phenyl-4-((3-(trifluoromethyl)benzyl)amino)butan-2-yl)-N3 ,5-dimethyl-N3 -((R)-1-phenylethyl)isophthalamide; Ki =1.6?nm, selectivity over BACE1: >500-fold] displayed outstanding potency and selectivity. Inhibitor 3?l is nonpeptide in nature and may pave the way to the development of a new class of potent and selective BACE2 inhibitors with clinical potential.

SUBMITTER: Ghosh AK 

PROVIDER: S-EPMC6637425 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature