title: Discovery of SCH 900229, a Potent Presenilin 1 Selective γ-Secretase Inhibitor for the Treatment of Alzheimer's Disease.
abstract: An exploration of the SAR of the side chain of a novel tricyclic series of γ-secretase inhibitors led to the identification of compound (-)-16 (SCH 900229), which is a potent and PS1 selective inhibitor of γ-secretase (Aβ40 IC50 = 1.3 nM). Compound (-)-16 demonstrated excellent lowering of Aβ after oral administration in preclinical animal models and was advanced to human clinical trials for further development as a therapeutic agent for the treatment of Alzheimer's disease.
authors.affiliation: Department of Medicinal Chemistry, Department of Neuroscience, Department of Pharmaceutical Sciences, and Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Wen-Lian
authors.initials: WL
authors.lastname: Wu
authors.affiliation: Department of Medicinal Chemistry, Department of Neuroscience, Department of Pharmaceutical Sciences, and Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Martin
authors.initials: M
authors.lastname: Domalski
authors.affiliation: Department of Medicinal Chemistry, Department of Neuroscience, Department of Pharmaceutical Sciences, and Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Duane A
authors.initials: DA
authors.lastname: Burnett
authors.affiliation: Department of Medicinal Chemistry, Department of Neuroscience, Department of Pharmaceutical Sciences, and Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Hubert
authors.initials: H
authors.lastname: Josien
authors.affiliation: Department of Medicinal Chemistry, Department of Neuroscience, Department of Pharmaceutical Sciences, and Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bara
authors.affiliation: Department of Medicinal Chemistry, Department of Neuroscience, Department of Pharmaceutical Sciences, and Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Murali
authors.initials: M
authors.lastname: Rajagopalan
authors.affiliation: Department of Medicinal Chemistry, Department of Neuroscience, Department of Pharmaceutical Sciences, and Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Ruo
authors.initials: R
authors.lastname: Xu
authors.affiliation: Department of Medicinal Chemistry, Department of Neuroscience, Department of Pharmaceutical Sciences, and Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: John
authors.initials: J
authors.lastname: Clader
authors.affiliation: Department of Medicinal Chemistry, Department of Neuroscience, Department of Pharmaceutical Sciences, and Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenlee
authors.affiliation: Department of Medicinal Chemistry, Department of Neuroscience, Department of Pharmaceutical Sciences, and Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Brunskill
authors.affiliation: Department of Medicinal Chemistry, Department of Neuroscience, Department of Pharmaceutical Sciences, and Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Hyde
authors.affiliation: Department of Medicinal Chemistry, Department of Neuroscience, Department of Pharmaceutical Sciences, and Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Del Vecchio
authors.affiliation: Department of Medicinal Chemistry, Department of Neuroscience, Department of Pharmaceutical Sciences, and Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Cohen-Williams
authors.affiliation: Department of Medicinal Chemistry, Department of Neuroscience, Department of Pharmaceutical Sciences, and Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Lixin
authors.initials: L
authors.lastname: Song
authors.affiliation: Department of Medicinal Chemistry, Department of Neuroscience, Department of Pharmaceutical Sciences, and Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Julie
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Medicinal Chemistry, Department of Neuroscience, Department of Pharmaceutical Sciences, and Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Terracina
authors.affiliation: Department of Medicinal Chemistry, Department of Neuroscience, Department of Pharmaceutical Sciences, and Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, Department of Neuroscience, Department of Pharmaceutical Sciences, and Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Amin
authors.initials: A
authors.lastname: Nomeir
authors.affiliation: Department of Medicinal Chemistry, Department of Neuroscience, Department of Pharmaceutical Sciences, and Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Parker
authors.affiliation: Department of Medicinal Chemistry, Department of Neuroscience, Department of Pharmaceutical Sciences, and Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
keywords: Alzheimer’s disease; amyloid; clinical candidate; notch; γ-Secretase inhibitor