title: Acylguanidine inhibitors of beta-secretase: optimization of the pyrrole ring substituents extending into the S1 and S3 substrate binding pockets.
abstract: Proteolytic cleavage of amyloid precursor protein by beta-secretase (BACE-1) and gamma-secretase leads to formation of beta-amyloid (A beta) a key component of amyloid plaques, which are considered the hallmark of Alzheimer's disease. Small molecule inhibitors of BACE-1 may reduce levels of A beta and thus have therapeutic potential for treating Alzheimer's disease. We recently reported the identification of a novel small molecule BACE-1 inhibitor N-[2-(2,5-diphenyl-pyrrol-1-yl)-acetyl]guanidine (3.a.1). We report here the initial hit-to-lead optimization of this hit and the SAR around the aryl groups occupying the S(1) and S(2') pockets leading to submicromolar BACE-1 inhibitors.
authors.affiliation: Chemical & Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. coledc@wyeth.com
authors.forename: Derek C
authors.initials: DC
authors.lastname: Cole
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Stock
authors.forename: Rajiv
authors.initials: R
authors.lastname: Chopra
authors.forename: Rebecca
authors.initials: R
authors.lastname: Cowling
authors.forename: John W
authors.initials: JW
authors.lastname: Ellingboe
authors.forename: Kristi Y
authors.initials: KY
authors.lastname: Fan
authors.forename: Boyd L
authors.initials: BL
authors.lastname: Harrison
authors.forename: Yun
authors.initials: Y
authors.lastname: Hu
authors.forename: Steve
authors.initials: S
authors.lastname: Jacobsen
authors.forename: Lee D
authors.initials: LD
authors.lastname: Jennings
authors.forename: Guixian
authors.initials: G
authors.lastname: Jin
authors.forename: Peter A
authors.initials: PA
authors.lastname: Lohse
authors.forename: Michael S
authors.initials: MS
authors.lastname: Malamas
authors.forename: Eric S
authors.initials: ES
authors.lastname: Manas
authors.forename: William J
authors.initials: WJ
authors.lastname: Moore
authors.forename: Mary-Margaret
authors.initials: MM
authors.lastname: O'Donnell
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Olland
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Robichaud
authors.forename: Kristine
authors.initials: K
authors.lastname: Svenson
authors.forename: JunJun
authors.initials: J
authors.lastname: Wu
authors.forename: Eric
authors.initials: E
authors.lastname: Wagner
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bard
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008968:Molecular Conformation; D015394:Molecular Structure; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D006146:Guanidines; C527343:N-(2-(2,5-diphenyl-pyrrol-1-yl)-acetyl)guanidine; D011758:Pyrroles; D053829:Amyloid Precursor Protein Secretases