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Discovery of BIIB042, a Potent, Selective, and Orally Bioavailable γ-Secretase Modulator.
Peng, Hairuo; Talreja, Tina; Xin, Zhili; Cuervo, J Hernan; Kumaravel, Gnanasambandam; Humora, Michael J; Xu, Lin; Rohde, Ellen; Gan, Lawrence; Jung, Mi-Young; Shackett, Melanie N; Chollate, Sowmya; Dunah, Anthone W; Snodgrass-Belt, Pamela A; Arnold, H Moore; Taveras, Arthur G; Rhodes, Kenneth J; Scannevin, Robert H.
Afiliação
  • Peng H; Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
  • Talreja T; Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
  • Xin Z; Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
  • Cuervo JH; Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
  • Kumaravel G; Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
  • Humora MJ; Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
  • Xu L; Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
  • Rohde E; Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
  • Gan L; Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
  • Jung MY; Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
  • Shackett MN; Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
  • Chollate S; Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
  • Dunah AW; Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
  • Snodgrass-Belt PA; Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
  • Arnold HM; Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
  • Taveras AG; Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
  • Rhodes KJ; Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
  • Scannevin RH; Departments of Medicinal Chemistry, Chemical Process, Drug Metabolism and Pharmacokinetics, and Neurology Research, Biogen Idec Inc. , 14 Cambridge Center, Cambridge, Massachusetts 02142, United States.
ACS Med Chem Lett ; 2(10): 786-91, 2011 Oct 13.
Article em En | MEDLINE | ID: mdl-24900267
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 Aß42, increased Aß38, but had little to no effect on Aß40 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 Aß42 levels in CF-1 mice and Fischer rats, as well as plasma Aß42 levels in cynomolgus monkeys. Compound 10a was selected as a candidate for preclinical safety evaluation.
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2011 Tipo de documento: Article
Texto completo
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PubMed Links
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2011 Tipo de documento: Article