title: Phe*-Ala-based pentapeptide mimetics are BACE inhibitors: P2 and P3 SAR.
abstract: We describe herein the syntheses and evaluation of a series of C-termini pyridyl containing Phe*-Ala-based BACE inhibitors (5-19). In conjunction with four fixed residues at the P1 (Phe), P1' (Ala), P2' (Val), and P2' cap (Pyr.), rather detailed SAR modifications at P2 and P3 positions were pursued. The promising inhibitors emerging from this SAR investigation, 12 and 17 demonstrated very good enzyme potency (IC(50)=45 nM) and cellular activity (IC(50)=0.4 microM).
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Lamar
authors.forename: Jingdan
authors.initials: J
authors.lastname: Hu
authors.forename: Ana Belen
authors.initials: AB
authors.lastname: Bueno
authors.forename: Hsiu-Chiung
authors.initials: HC
authors.lastname: Yang
authors.forename: Deqi
authors.initials: D
authors.lastname: Guo
authors.forename: James D
authors.initials: JD
authors.lastname: Copp
authors.forename: James
authors.initials: J
authors.lastname: McGee
authors.forename: Bruce
authors.initials: B
authors.lastname: Gitter
authors.forename: David
authors.initials: D
authors.lastname: Timm
authors.forename: Patrick
authors.initials: P
authors.lastname: May
authors.forename: James
authors.initials: J
authors.lastname: McCarthy
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Chen
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D002460:Cell Line; D004151:Dipeptides / Q000138:chemical synthesis* / Q000633:toxicity; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D018716:Molecular Mimicry; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D004151:Dipeptides; D011480:Protease Inhibitors; C039552:phenylalanylalanine; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human