title: Acylguanidine inhibitors of beta-secretase: optimization of the pyrrole ring substituents extending into the S1' substrate binding pocket.
abstract: The proteolytic enzyme beta-secretase (BACE-1) produces amyloid beta (Abeta) peptide, the primary constituent of neurofibrillary plaques, implicated in Alzheimer's disease, by cleavage of the amyloid precursor protein. A small molecule inhibitor of BACE-1, (diaminomethylene)-2,5-diphenyl-1H-pyrrole-1-acetamide (1, BACE-1 IC(50)=3.7 microM), was recently described, representing a new small molecule lead. Initial SAR investigation demonstrated the potential of accessing the nearby S(3) and S(1)(') substrate binding pockets of the BACE-1 enzyme by building substituents off one of the phenyl substituents and guanidinyl functional group. We report here the optimization of guanidinyl functional group substituents on 1, leading to potent submicromolar BACE-1 inhibitors.
authors: Chemical & Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. jenninl@wyeth.com
authors: Lee D
authors: LD
authors: Jennings
authors: Derek C
authors: DC
authors: Cole
authors: Joseph R
authors: JR
authors: Stock
authors: Mohani N
authors: MN
authors: Sukhdeo
authors: John W
authors: JW
authors: Ellingboe
authors: Rebecca
authors: R
authors: Cowling
authors: Guixian
authors: G
authors: Jin
authors: Eric S
authors: ES
authors: Manas
authors: Kristi Y
authors: KY
authors: Fan
authors: Michael S
authors: MS
authors: Malamas
authors: Boyd L
authors: BL
authors: Harrison
authors: Steve
authors: S
authors: Jacobsen
authors: Rajiv
authors: R
authors: Chopra
authors: Peter A
authors: PA
authors: Lohse
authors: William J
authors: WJ
authors: Moore
authors: Mary-Margaret
authors: MM
authors: O'Donnell
authors: Yun
authors: Y
authors: Hu
authors: Albert J
authors: AJ
authors: Robichaud
authors: M James
authors: MJ
authors: Turner
authors: Erik
authors: E
authors: Wagner
authors: Jonathan
authors: J
authors: Bard
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D019791:Guanidine / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D011758:Pyrroles / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D011758:Pyrroles; D053829:Amyloid Precursor Protein Secretases; D019791:Guanidine