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

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 >100x more potent than 1, such as 7 (5 nM K(i)).

DOI: 10.1016/j.bmcl.2010.03.097

5 Figures and Tables

Cite this paper

@article{Huang2010MacrocyclicBI, title={Macrocyclic BACE inhibitors: Optimization of a micromolar hit to nanomolar leads.}, author={Yifang Huang and Eric D Strobel and Chih Ho and Charles H. Reynolds and Kelly A. Conway and Jennifer A Piesvaux and Douglas E . Brenneman and George J Yohrling and H Moore Arnold and Daniel I. Rosenthal and Richard S Alexander and Brett A. Tounge and Marc H Mercken and Marc Vandermeeren and Michael H Parker and Allen B. Reitz and Ellen W Baxter}, journal={Bioorganic & medicinal chemistry letters}, year={2010}, volume={20 10}, pages={3158-60} }