New pyrazolyl and thienyl aminohydantoins as potent BACE1 inhibitors: Exploring the S2′ region

…, W Solvibile, J Turner, KY Fan, R Chopra, J Bard…

Index: Malamas, Michael S.; Erdei, Jim; Gunawan, Iwan; Barnes, Keith; Hui, Yu; Johnson, Matthew; Robichaud, Albert; Zhou, Ping; Yan, Yinfa; Solvibile, William; Turner, Jim; Fan, Kristi Yi; Chopra, Rajiv; Bard, Jonathan; Pangalos, Menelas N. Bioorganic and Medicinal Chemistry Letters, 2011 , vol. 21, # 18 p. 5164 - 5170

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Citation Number: 14

Abstract

The proteolytic enzyme β-secretase (BACE1) plays a central role in the synthesis of the pathogenic β-amyloid in Alzheimer's disease. SAR studies of the S2′ region of the BACE1 ligand binding pocket with pyrazolyl and thienyl P2′ side chains are reported. These analogs exhibit low nanomolar potency for BACE1, and demonstrate> 50-to 100-fold selectivity for the structurally related aspartyl proteases BACE2 and cathepsin D. Small ...