title: Design and synthesis of aminothiazole modulators of the gamma-secretase enzyme.
abstract: The design and construction of a series of novel aminothiazole-derived γ-secretase modulators is described. The incorporation of heterocyclic replacements of the terminal phenyl D-ring of lead compound 1 was conducted in order to align potency with favorable drug-like properties. γ-Secretase modulator 28 displayed good activity for in vitro inhibition of Aβ42, as well as substantial improvement in ADME and physicochemical properties, including aqueous solubility. Pharmacokinetic evaluation of compound 28 in mice revealed good brain penetration, as well as good clearance, half-life, and volume of distribution which collectively support the continued development of this class of compounds.
authors.affiliation: Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive MC 0624, La Jolla, CA 92093-0624, United States.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Rynearson
authors.affiliation: Department of Medicinal Chemistry, AMRI, East Campus, 3 University Place, Rensselaer, NY 12144, United States.
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Buckle
authors.affiliation: Department of Medicinal Chemistry, AMRI, East Campus, 3 University Place, Rensselaer, NY 12144, United States.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Barnes
authors.affiliation: Department of Medicinal Chemistry, AMRI, East Campus, 3 University Place, Rensselaer, NY 12144, United States.
authors.forename: R Jason
authors.initials: RJ
authors.lastname: Herr
authors.affiliation: Department of Medicinal Chemistry, AMRI, East Campus, 3 University Place, Rensselaer, NY 12144, United States.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Mayhew
authors.affiliation: Department of Medicinal Chemistry, AMRI, East Campus, 3 University Place, Rensselaer, NY 12144, United States.
authors.forename: William D
authors.initials: WD
authors.lastname: Paquette
authors.affiliation: Department of Medicinal Chemistry, AMRI, East Campus, 3 University Place, Rensselaer, NY 12144, United States.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Sakwa
authors.affiliation: Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive MC 0624, La Jolla, CA 92093-0624, United States.
authors.forename: Phuong D
authors.initials: PD
authors.lastname: Nguyen
authors.affiliation: NuPharmAdvise, 3 Lakeside Drive, Sanbornton, NH 03269, United States.
authors.forename: Graham
authors.initials: G
authors.lastname: Johnson
authors.affiliation: Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, United States.
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
authors.affiliation: Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive MC 0624, La Jolla, CA 92093-0624, United States. Electronic address: slwagner@ucsd.edu.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Wagner
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D015195:Drug Design; D006207:Half-Life; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer’s disease; Aminothiazoles; γ-Secretase modulators