2. Academic Validation
  3. Discovery of BIIB042, a Potent, Selective, and Orally Bioavailable γ-Secretase Modulator

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

  • ACS Med Chem Lett. 2011 Aug 5;2(10):786-91. doi: 10.1021/ml200175q.
Hairuo Peng 1,  Tina Talreja 1,  Zhili Xin 1,  J Hernan Cuervo 1,  Gnanasambandam Kumaravel 1,  Michael J Humora 1,  Lin Xu 1,  Ellen Rohde 1,  Lawrence Gan 1,  Mi-Young Jung 1,  Melanie N Shackett 1,  Sowmya Chollate 1,  Anthone W Dunah 1,  Pamela A Snodgrass-Belt 1,  H Moore Arnold 1,  Arthur G Taveras 1,  Kenneth J Rhodes 1,  Robert H Scannevin 1
Affiliations

Affiliation

  • 1 Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
PMID: 24900267 DOI: 10.1021/ml200175q
Abstract

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 demonstrated excellent pharmacokinetic parameters in multiple species. Oral administration of 10a significantly reduced brain Aβ42 levels in CF-1 mice and Fischer rats, as well as plasma Aβ42 levels in cynomolgus monkeys. Compound 10a was selected as a candidate for preclinical safety evaluation.

Keywords

Alzheimer's; GSM; Mannich reaction; Secretase; amyloid.

Figures
Products