title: P3 cap modified Phe*-Ala series BACE inhibitors.
abstract: With the aim of reducing molecular weight and adjusting log D value of BACE inhibitors to more favorable range for BBB penetration and better bioavailability, we synthesized and evaluated several series of P3 cap modified BACE inhibitors obtained via replacement of the P3NHBoc moiety as seen in 3 with other polar functional groups such as amino, hydroxyl and fluorine. Several promising inhibitors emerging from this P3 cap SAR study (e.g., 15 and 19) demonstrated good enzyme inhibitory potencies (BACE-1 IC(50) <50 nM) and whole cell activities (IC(50) approximately 1 microM).
authors.affiliation: Lilly Research Laboratories, Discovery Chemistry Division and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. chen_shu-hui@lilly.com
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Chen
authors.forename: Jason
authors.initials: J
authors.lastname: Lamar
authors.forename: Deqi
authors.initials: D
authors.lastname: Guo
authors.forename: Todd
authors.initials: T
authors.lastname: Kohn
authors.forename: Hsiu-Chiung
authors.initials: HC
authors.lastname: Yang
authors.forename: James
authors.initials: J
authors.lastname: McGee
authors.forename: David
authors.initials: D
authors.lastname: Timm
authors.forename: Jon
authors.initials: J
authors.lastname: Erickson
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Yip
authors.forename: Patrick
authors.initials: P
authors.lastname: May
authors.forename: James
authors.initials: J
authors.lastname: McCarthy
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D002460:Cell Line; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology*; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004151:Dipeptides; D011480:Protease Inhibitors; C039552:phenylalanylalanine; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human