title: Discovery of benzodiazepine sulfonamide-based bombesin receptor subtype 3 agonists and their unusual chirality.
abstract: We report herein the discovery of benzodiazepine sulfonamide-based bombesin receptor subtype 3 (BRS-3) agonists and their unusual chirality. Starting from a high-throughput screening lead, we prepared a series of BRS-3 agonists with improved potency and pharmacokinetic properties, of which compound 8a caused mechanism-based, dose-dependent food intake reduction and body weight loss after oral dosing in diet-induced obese mice. This effort also led to the discovery of a novel family of chiral molecules originated from the conformationally constrained seven-membered diazepine ring.
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Lanza
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Marc
authors.initials: M
authors.lastname: Chioda
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Carrie
authors.initials: C
authors.lastname: Jones
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Harry R
authors.initials: HR
authors.lastname: Chobanian
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Linda
authors.initials: L
authors.lastname: Chang
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Kelly
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Kan
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Oksana
authors.initials: O
authors.lastname: Palyha
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Guan
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Marsh
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Metzger
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Katie
authors.initials: K
authors.lastname: Ramsay
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Sheng-Ping
authors.initials: SP
authors.lastname: Wang
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Strack
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Randy
authors.initials: R
authors.lastname: Miller
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Jianmei
authors.initials: J
authors.lastname: Pang
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Kathy
authors.initials: K
authors.lastname: Lyons
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Jasminka
authors.initials: J
authors.lastname: Dragovic
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Jian G
authors.initials: JG
authors.lastname: Ning
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Wes A
authors.initials: WA
authors.lastname: Schafer
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Welch
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Gong
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Ying-Duo
authors.initials: YD
authors.lastname: Gao
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Viktor
authors.initials: V
authors.lastname: Hornak
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Ball
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Nancy
authors.initials: N
authors.lastname: Tsou
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Marc L
authors.initials: ML
authors.lastname: Reitman
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Wyvratt
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Ravi P
authors.initials: RP
authors.lastname: Nargund
authors.affiliation: Departments of Medicinal Chemistry, Metabolic Disorders, Pharmacology, Drug Metabolism, Analytic Chemistry, Chemistry Modeling & Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Linus S
authors.initials: LS
authors.lastname: Lin
keywords: BRS-3; Bombesin receptor subtype 3; agonist; atropisomerism; benzodiazepine sulfonamide; obesity; planar chirality