Structure- and Property-Based Design of Aminooxazoline Xanthenes as Selective, Orally Efficacious, and CNS Penetrable BACE Inhibitors for the Treatment of Alzheimer’s Disease
Journal of Medicinal Chemistry2012Vol. 55(21), pp. 9156–9169
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Hongbing Huang, Daniel S. La, Alan C. Cheng, Douglas A. Whittington, Vinod F. Patel, Kui Chen, Thomas A. Dineen, O. I. Epstein, Russell F. Graceffa, Dean Hickman, Y.-H. Kiang, Steven W. Louie, Yi Luo, Robert C. Wahl, Paul H. Wen, Stephen Wood, Robert T. Fremeau
Abstract
A structure- and property-based drug design approach was employed to identify aminooxazoline xanthenes as potent and selective human β-secretase inhibitors. These compounds exhibited good isolated enzyme, cell potency, and selectivity against the structurally related aspartyl protease cathepsin D. Our efforts resulted in the identification of a potent, orally bioavailable CNS penetrant compound that exhibited in vivo efficacy. A single oral dose of compound 11a resulted in a significant reduction of CNS Aβ40 in naive rats.
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