title: Discovery of 4-aminomethylphenylacetic acids as γ-secretase modulators via a scaffold design approach.
abstract: Starting from literature examples of nonsteroidal anti-inflammatory drugs (NSAIDs)-type carboxylic acid γ-secretase modulators (GSMs) and using a scaffold design approach, we identified 4-aminomethylphenylacetic acid 4 with a desirable γ-secretase modulation profile. Scaffold optimization led to the discovery of a novel chemical series, represented by 6b, having improved brain penetration. Further SAR studies provided analog 6q that exhibited a good pharmacological profile. Oral administration of 6q significantly reduced brain Aβ42 levels in mice and rats.
authors: Department of Medicinal Chemistry, Biogen Idec Inc., 14 Cambridge Center, Cambridge, MA 02142, USA. zhili.xin@biogenidec.com
authors: Zhili
authors: Z
authors: Xin
authors: Hairuo
authors: H
authors: Peng
authors: Andrew
authors: A
authors: Zhang
authors: Tina
authors: T
authors: Talreja
authors: Gnanasambandam
authors: G
authors: Kumaravel
authors: Lin
authors: L
authors: Xu
authors: Ellen
authors: E
authors: Rohde
authors: Mi-yong
authors: MY
authors: Jung
authors: Melanie N
authors: MN
authors: Shackett
authors: David
authors: D
authors: Kocisko
authors: Sowmya
authors: S
authors: Chollate
authors: Anthone W
authors: AW
authors: Dunah
authors: Pamela A
authors: PA
authors: Snodgrass-Belt
authors: H Moore
authors: HM
authors: Arnold
authors: Arthur G
authors: AG
authors: Taveras
authors: Kenneth J
authors: KJ
authors: Rhodes
authors: Robert H
authors: RH
authors: Scannevin
mesh_terms: D000284:Administration, Oral; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001921:Brain / Q000378:metabolism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism; D010648:Phenylacetates / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D010648:Phenylacetates; D010880:Piperidines; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; C025136:phenylacetic acid