title: Discovery of BIIB042, a Potent, Selective, and Orally Bioavailable γ-Secretase Modulator.
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.
authors.affiliation: Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Hairuo
authors.initials: H
authors.lastname: Peng
authors.affiliation: Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Tina
authors.initials: T
authors.lastname: Talreja
authors.affiliation: Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Zhili
authors.initials: Z
authors.lastname: Xin
authors.affiliation: Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: J Hernan
authors.initials: JH
authors.lastname: Cuervo
authors.affiliation: Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Gnanasambandam
authors.initials: G
authors.lastname: Kumaravel
authors.affiliation: Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Humora
authors.affiliation: Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.affiliation: Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Ellen
authors.initials: E
authors.lastname: Rohde
authors.affiliation: Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Gan
authors.affiliation: Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Mi-Young
authors.initials: MY
authors.lastname: Jung
authors.affiliation: Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Melanie N
authors.initials: MN
authors.lastname: Shackett
authors.affiliation: Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Sowmya
authors.initials: S
authors.lastname: Chollate
authors.affiliation: Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Anthone W
authors.initials: AW
authors.lastname: Dunah
authors.affiliation: Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Snodgrass-Belt
authors.affiliation: Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: H Moore
authors.initials: HM
authors.lastname: Arnold
authors.affiliation: Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Arthur G
authors.initials: AG
authors.lastname: Taveras
authors.affiliation: Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Rhodes
authors.affiliation: Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Scannevin
keywords: Alzheimer's; GSM; Mannich reaction; Secretase; amyloid