Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor that Affords Robust CNS A? Reduction.

Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor that Affords Robust CNS A? Reduction.

ACS Med Chem Lett. 2012 Nov 8;3(11):897-902

Authors: Stamford AW, Scott JD, Li SW, Babu S, Tadesse D, Hunter R, Wu Y, Misiaszek J, Cumming JN, Gilbert EJ, Huang C, McKittrick BA, Hong L, Guo T, Zhu Z, Strickland C, Orth P, Voigt JH, Kennedy ME, Chen X, Kuvelkar R, Hodgson R, Hyde LA, Cox K, Favreau L, Parker EM, Greenlee WJ

Abstract
Inhibition of BACE1 to prevent brain A? peptide formation is a potential disease-modifying approach to the treatment of Alzheimer's disease. Despite over a decade of drug discovery efforts, the identification of brain-penetrant BACE1 inhibitors that substantially lower CNS A? levels following systemic administration remains challenging. In this report we describe structure-based optimization of a series of brain-penetrant BACE1 inhibitors derived from an iminopyrimidinone scaffold. Application of structure-based design in tandem with control of physicochemical properties culminated in the discovery of compound 16, which potently reduced cortex and CSF A?40 levels when administered orally to rats.

PMID: 23412139 [PubMed - as supplied by publisher]

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