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Highly Selective and Potent Human β‐Secretase 2 (BACE2) Inhibitors against Type 2 Diabetes: Design, Synthesis, X‐ray Structure and Structure–Activity Relationship Studies
Author(s) -
Ghosh Arun K.,
Brindisi Margherita,
Yen YuChen,
Lendy Emma K.,
Kovela Satish,
Cárdenas Emilio Leal,
Reddy Bhavanam Sekhara,
Rao Kalapala Venketeswara,
Downs Deborah,
Huang Xiangping,
Tang Jordan,
Mesecar Andrew D.
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800725
Subject(s) - chemistry , stereochemistry , selectivity , isostere , potency , enzyme , trifluoromethyl , docking (animal) , biochemistry , in vitro , organic chemistry , catalysis , medicine , alkyl , nursing
Herein we present the design, synthesis, and biological evaluation of potent and highly selective β‐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 { N 3 ‐[(1 S ,2 R )‐1‐benzyl‐2‐hydroxy‐3‐[[(1 S ,2 S )‐2‐hydroxy‐1‐(isobutylcarbamoyl)propyl]amino]propyl]‐5‐[methyl(methylsulfonyl)amino]‐ N 1 ‐[(1 R )‐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 [ N 3 ‐[(1 S ,2 R )‐1‐benzyl‐2‐hydroxy‐3‐[[(1 S ,2 S )‐2‐hydroxy‐1‐(isobutylcarbamoyl)pentyl]amino]propyl]‐ N 1 ‐methyl‐ N 1 ‐[(1 R )‐1‐phenylpropyl]benzene‐1,3‐dicarboxamide; K i =0.031 n m , selectivity over BACE1: ≈174 000‐fold] and 3 l [ N 1 ‐((2 S ,3 R )‐3‐hydroxy‐1‐phenyl‐4‐((3‐(trifluoromethyl)benzyl)amino)butan‐2‐yl)‐ N 3 ,5‐dimethyl‐ N 3 ‐(( R )‐1‐phenylethyl)isophthalamide; K i =1.6 n m , 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.