title: Discovery of Novel Indoline Cholesterol Ester Transfer Protein Inhibitors (CETP) through a Structure-Guided Approach.
abstract: Using the collective body of known (CETP) inhibitors as inspiration for design, a structurally novel series of tetrahydroquinoxaline CETP inhibitors were discovered. An exemplar from this series, compound 5, displayed potent in vitro CETP inhibition and was efficacious in a transgenic cynomologus-CETP mouse HDL PD (pharmacodynamic) assay. However, an undesirable metabolic profile and chemical instability hampered further development of the series. A three-dimensional structure of tetrahydroquinoxaline inhibitor 6 was proposed from (1)H NMR structural studies, and this model was then used in silico for the design of a new class of compounds based upon an indoline scaffold. This work resulted in the discovery of compound 7, which displayed potent in vitro CETP inhibition, a favorable PK-PD profile relative to tetrahydroquinoxaline 5, and dose-dependent efficacy in the transgenic cynomologus-CETP mouse HDL PD assay.
authors.affiliation: Department of Medicinal Chemistry and Department of Structural Chemistry, Merck Research Laboratories, Merck & Co, Inc. , P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Wilson
authors.affiliation: Department of Medicinal Chemistry and Department of Structural Chemistry, Merck Research Laboratories, Merck & Co, Inc. , P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Ravi
authors.initials: R
authors.lastname: Kurukulasuriya
authors.affiliation: Department of Medicinal Chemistry and Department of Structural Chemistry, Merck Research Laboratories, Merck & Co, Inc. , P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Reibarkh
authors.affiliation: Department of Medicinal Chemistry and Department of Structural Chemistry, Merck Research Laboratories, Merck & Co, Inc. , P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Maud
authors.initials: M
authors.lastname: Reiter
authors.affiliation: Department of Medicinal Chemistry and Department of Structural Chemistry, Merck Research Laboratories, Merck & Co, Inc. , P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Aaron
authors.initials: A
authors.lastname: Zwicker
authors.affiliation: Department of Medicinal Chemistry and Department of Structural Chemistry, Merck Research Laboratories, Merck & Co, Inc. , P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Kake
authors.initials: K
authors.lastname: Zhao
authors.affiliation: Department of Medicinal Chemistry and Department of Structural Chemistry, Merck Research Laboratories, Merck & Co, Inc. , P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Fengqi
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry and Department of Structural Chemistry, Merck Research Laboratories, Merck & Co, Inc. , P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Rajan
authors.initials: R
authors.lastname: Anand
authors.affiliation: Department of Medicinal Chemistry and Department of Structural Chemistry, Merck Research Laboratories, Merck & Co, Inc. , P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Colandrea
authors.affiliation: Department of Pharmacology, Department of Drug Metabolism and Pharmacokinetics, and Department of Biology, Merck Research Laboratories, Merck & Co, Inc. , P.O. Box 2000, Kenilworth, New Jersey 07033, United States.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Cumiskey
authors.affiliation: Department of Medicinal Chemistry and Department of Structural Chemistry, Merck Research Laboratories, Merck & Co, Inc. , P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Crespo
authors.affiliation: Department of Pharmacology, Department of Drug Metabolism and Pharmacokinetics, and Department of Biology, Merck Research Laboratories, Merck & Co, Inc. , P.O. Box 2000, Kenilworth, New Jersey 07033, United States.
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Duffy
authors.affiliation: Department of Pharmacology, Department of Drug Metabolism and Pharmacokinetics, and Department of Biology, Merck Research Laboratories, Merck & Co, Inc. , P.O. Box 2000, Kenilworth, New Jersey 07033, United States.
authors.forename: Beth Ann
authors.initials: BA
authors.lastname: Murphy
authors.affiliation: Department of Pharmacology, Department of Drug Metabolism and Pharmacokinetics, and Department of Biology, Merck Research Laboratories, Merck & Co, Inc. , P.O. Box 2000, Kenilworth, New Jersey 07033, United States.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Mitra
authors.affiliation: Department of Pharmacology, Department of Drug Metabolism and Pharmacokinetics, and Department of Biology, Merck Research Laboratories, Merck & Co, Inc. , P.O. Box 2000, Kenilworth, New Jersey 07033, United States.
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Johns
authors.affiliation: Department of Medicinal Chemistry and Department of Structural Chemistry, Merck Research Laboratories, Merck & Co, Inc. , P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Duffy
authors.affiliation: Department of Medicinal Chemistry and Department of Structural Chemistry, Merck Research Laboratories, Merck & Co, Inc. , P.O. Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Petr
authors.initials: P
authors.lastname: Vachal
keywords: CETP inhibition; HDL; cholesterol ester transfer protein; indoline; tetrahydroquinoxaline