title: Part 1: Notch-sparing γ-secretase inhibitors: The identification of novel naphthyl and benzofuranyl amide analogs.
abstract: γ-Secretase is one of two proteases directly involved in the production of the amyloid β-peptide (Aβ), which is pathogenic in Alzheimer's disease. Inhibition of γ-secretase to suppress the production of Aβ should not block processing of one of its alternative substrates, Notch1 receptors, as interference with Notch1 signaling leads to severe toxic effects. In the course of our studies to identify γ-secretase inhibitors with selectivity for APP over Notch, 1 [3-(benzyl(isopropyl)amino)-1-(naphthalen-2-yl)propan-1-one] was found to inhibit γ-secretase-mediated Aβ production without interfering with γ-secretase-mediated Notch processing in purified enzyme assays. As 1 is chemically unstable, efforts to increase the stability of this compound led to the identification of 2 [naphthalene-2-carboxylic acid benzyl-isopropyl-amide] which showed similar biological activity to compound 1. Synthesis and evaluation of a series of amide analogs resulted in benzofuranyl amide analogs that showed promising Notch-sparing γ-secretase inhibitory effects. This class of compounds may serve as a novel lead series for further study in the development of γ-secretase inhibitors.
authors.affiliation: Laboratory for Experimental Alzheimer Drugs (LEAD), Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Harvard Institutes of Medicine, Boston, MA 02115, United States.
authors.forename: Dai
authors.initials: D
authors.lastname: Lu
authors.affiliation: Laboratory for Experimental Alzheimer Drugs (LEAD), Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Harvard Institutes of Medicine, Boston, MA 02115, United States.
authors.forename: Han-Xun
authors.initials: HX
authors.lastname: Wei
authors.affiliation: Laboratory for Experimental Alzheimer Drugs (LEAD), Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Harvard Institutes of Medicine, Boston, MA 02115, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Laboratory for Experimental Alzheimer Drugs (LEAD), Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Harvard Institutes of Medicine, Boston, MA 02115, United States.
authors.forename: Yongli
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Laboratory for Experimental Alzheimer Drugs (LEAD), Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Harvard Institutes of Medicine, Boston, MA 02115, United States.
authors.forename: Pamela
authors.initials: P
authors.lastname: Osenkowski
authors.affiliation: Laboratory for Experimental Alzheimer Drugs (LEAD), Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Harvard Institutes of Medicine, Boston, MA 02115, United States.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Ye
authors.affiliation: Laboratory for Experimental Alzheimer Drugs (LEAD), Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Harvard Institutes of Medicine, Boston, MA 02115, United States.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Selkoe
authors.affiliation: Laboratory for Experimental Alzheimer Drugs (LEAD), Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Harvard Institutes of Medicine, Boston, MA 02115, United States.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wolfe
authors.affiliation: Laboratory for Experimental Alzheimer Drugs (LEAD), Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Harvard Institutes of Medicine, Boston, MA 02115, United States. Electronic address: caugelli-szafran@southernresearch.org.
authors.forename: Corinne E
authors.initials: CE
authors.lastname: Augelli-Szafran
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors; D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis / Q000494:pharmacology*; D001596:Benzylamines / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D009281:Naphthalenes / Q000138:chemical synthesis / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: C000621343:3-(benzyl(isopropyl)amino)-1-(naphthalen-2-yl)propan-1-one; D000577:Amides; D016229:Amyloid beta-Peptides; D001572:Benzofurans; D001596:Benzylamines; C497761:NOTCH1 protein, human; D009281:Naphthalenes; C497763:Notch1 protein, rat; D010446:Peptide Fragments; D011480:Protease Inhibitors; D051881:Receptor, Notch1; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer’s disease; Aβ production; Naphthyl amides; Notch processing; γ-Secretase inhibitors