Macrocyclic BACE inhibitors: Optimization of a micromolar hit to nanomolar leads

…, D Rosenthal, RS Alexander, BA Tounge…

Index: Huang, Yifang; Strobel, Eric D.; Ho, Chih Y.; Reynolds, Charles H.; Conway, Kelly A.; Piesvaux, Jennifer A.; Brenneman, Douglas E.; Yohrling, George J.; Moore Arnold; Rosenthal, Daniel; Alexander, Richard S.; Tounge, Brett A.; Mercken, Marc; Vandermeeren, Marc; Parker, Michael H.; Reitz, Allen B.; Baxter, Ellen W. Bioorganic and Medicinal Chemistry Letters, 2010 , vol. 20, # 10 p. 3158 - 3160

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Citation Number: 21

Abstract

We have identified macrocyclic inhibitors of the aspartic protease BACE, implicated in the etiology of Alzheimer's disease. An X-ray structure of screening hit 1 in the BACE active site revealed a hairpin conformation suggesting that constrained macrocyclic derivatives may also bind there. Several of the analogs we prepared were> 100× more potent than 1, such as 7 (5nM Ki).