title: Design and Synthesis of Novel, Selective GPR40 AgoPAMs.
abstract: GPR40 is a G-protein-coupled receptor expressed primarily in pancreatic islets and intestinal L-cells that has been a target of significant recent therapeutic interest for type II diabetes. Activation of GPR40 by partial agonists elicits insulin secretion only in the presence of elevated blood glucose levels, minimizing the risk of hypoglycemia. GPR40 agoPAMs have shown superior efficacy to partial agonists as assessed in a glucose tolerability test (GTT). Herein, we report the discovery and optimization of a series of potent, selective GPR40 agoPAMs. Compound24demonstrated sustained glucose lowering in a chronic study of Goto Kakizaki rats, showing no signs of tachyphylaxis for this mechanism.
authors.affiliation: Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Plummer
authors.affiliation: Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Clements
authors.affiliation: Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Helen
authors.initials: H
authors.lastname: Chen
authors.affiliation: Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Murali
authors.initials: M
authors.lastname: Rajagopalan
authors.affiliation: Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Hubert
authors.initials: H
authors.lastname: Josien
authors.affiliation: Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: William K
authors.initials: WK
authors.lastname: Hagmann
authors.affiliation: Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Miller
authors.affiliation: Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Trujillo
authors.affiliation: Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Melissa
authors.initials: M
authors.lastname: Kirkland
authors.affiliation: Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kosinski
authors.affiliation: Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Joel
authors.initials: J
authors.lastname: Mane
authors.affiliation: Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Michele
authors.initials: M
authors.lastname: Pachanski
authors.affiliation: Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Boonlert
authors.initials: B
authors.lastname: Cheewatrakoolpong
authors.affiliation: Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Nolting
authors.affiliation: Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Orr
authors.affiliation: Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Melodie
authors.initials: M
authors.lastname: Christensen
authors.affiliation: Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Louis-Charles
authors.initials: LC
authors.lastname: Campeau
authors.affiliation: Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wright
authors.affiliation: Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Randal
authors.initials: R
authors.lastname: Bugianesi
authors.affiliation: Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Souza
authors.affiliation: Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Jerry
authors.initials: J
authors.lastname: Di Salvo
authors.affiliation: Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Weinglass
authors.affiliation: Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Tschirret-Guth
authors.affiliation: Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Ravi
authors.initials: R
authors.lastname: Nargund
authors.affiliation: Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Howard
authors.affiliation: Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Colletti
keywords: FFA1; GPCR; GPR40; agoPAM; chroman; diabetes; insulin secretogogue