title: Design, Synthesis, and Evaluation of Novel and Selective G-protein Coupled Receptor 120 (GPR120) Spirocyclic Agonists.
abstract: Type 2 diabetes mellitus (T2DM) is an ever increasing worldwide epidemic, and the identification of safe and effective insulin sensitizers, absent of weight gain, has been a long-standing goal of diabetes research. G-protein coupled receptor 120 (GPR120) has recently emerged as a potential therapeutic target for treating T2DM. Natural occurring, and more recently, synthetic agonists have been associated with insulin sensitizing, anti-inflammatory, and fat metabolism effects. Herein we describe the design, synthesis, and evaluation of a novel spirocyclic GPR120 agonist series, which culminated in the discovery of potent and selective agonist14. Furthermore, compound14was evaluatedin vivoand demonstrated acute glucose lowering in an oral glucose tolerance test (oGTT), as well as improvements in homeostatic measurement assessment of insulin resistance (HOMA-IR; a surrogate marker for insulin sensitization) and an increase in glucose infusion rate (GIR) during a hyperinsulinemic euglycemic clamp in diet-induced obese (DIO) mice.
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Cox
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors.forename: Hong D
authors.initials: HD
authors.lastname: Chu
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors.forename: Mariappan V
authors.initials: MV
authors.lastname: Chelliah
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors.forename: John S
authors.initials: JS
authors.lastname: Debenham
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors.forename: Keith
authors.initials: K
authors.lastname: Eagen
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors.forename: Ping
authors.initials: P
authors.lastname: Lan
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors.forename: Matthew
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authors.lastname: Lombardo
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors.forename: Clare
authors.initials: C
authors.lastname: London
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Plotkin
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors.forename: Unmesh
authors.initials: U
authors.lastname: Shah
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors.forename: Zhongxiang
authors.initials: Z
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authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors.forename: Henry M
authors.initials: HM
authors.lastname: Vaccaro
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Venkatraman
authors.affiliation: WuXi AppTec , Shanghai, 200131, China.
authors.forename: Takao
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: WuXi AppTec , Shanghai, 200131, China.
authors.forename: Nengxue
authors.initials: N
authors.lastname: Wang
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Ashley
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
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authors.initials: A
authors.lastname: Crespo
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors.forename: Maria
authors.initials: M
authors.lastname: Madeira
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
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authors.initials: DH
authors.lastname: Leung
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors.forename: Candice
authors.initials: C
authors.lastname: Alleyne
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
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authors.initials: AM
authors.lastname: Ogawa
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
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authors.initials: S
authors.lastname: Souza
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
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authors.initials: B
authors.lastname: Thomas-Fowlkes
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
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authors.initials: J
authors.lastname: Di Salvo
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors.forename: Adam
authors.initials: A
authors.lastname: Weinglass
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
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authors.lastname: Kirkland
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
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authors.lastname: Pachanski
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Powles
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors.forename: Effie
authors.initials: E
authors.lastname: Tozzo
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors.forename: Taro E
authors.initials: TE
authors.lastname: Akiyama
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors.forename: Feroze
authors.initials: F
authors.lastname: Ujjainwalla
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors.forename: James R
authors.initials: JR
authors.lastname: Tata
authors.affiliation: Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., Inc., Rahway, New Jersey 07065, United States.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Sinz
keywords: FFAR4; GPR120; insulin sensitization; spirocyclic; type 2 diabetes