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Discovery of BIIB042, a Potent, Selective, and Orally Bioavailable ?-Secretase Modulator.

ABSTRACT: We have investigated a novel series of acid-derived ?-secretase modulators as a potential treatment of Alzheimer's disease. Optimization based on cellular potency and brain pharmacodynamics after oral dosing led to the discovery of 10a (BIIB042). Compound 10a is a potent ?-secretase modulator, which lowered A?42, increased A?38, but had little to no effect on A?40 levels both in vitro and in vivo. In addition, compound 10a did not affect Notch signaling in our in vitro assessment. Compound 10a demonstrated excellent pharmacokinetic parameters in multiple species. Oral administration of 10a significantly reduced brain A?42 levels in CF-1 mice and Fischer rats, as well as plasma A?42 levels in cynomolgus monkeys. Compound 10a was selected as a candidate for preclinical safety evaluation.

SUBMITTER: Peng H 

PROVIDER: S-EPMC4018072 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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We have investigated a novel series of acid-derived γ-secretase modulators as a potential treatment of Alzheimer's disease. Optimization based on cellular potency and brain pharmacodynamics after oral dosing led to the discovery of 10a (BIIB042). Compound 10a is a potent γ-secretase modulator, which lowered Aβ42, increased Aβ38, but had little to no effect on Aβ40 levels both in vitro and in vivo. In addition, compound 10a did not affect Notch signaling in our in vitro assessment. Compound 10a d  ...[more]

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