title: Discovery and Optimization of a Novel Triazole Series of GPR142 Agonists for the Treatment of Type 2 Diabetes.
abstract: GPR142 has been identified as a potential glucose-stimulated insulin secretion (GSIS) target for the treatment of type 2 diabetes mellitus (T2DM). A class of triazole GPR142 agonists was discovered through a high throughput screen. The lead compound4suffered from poor metabolic stability and poor solubility. Lead optimization strategies to improve potency, efficacy, metabolic stability, and solubility are described. This optimization led to compound20e, which showed significant reduction of glucose excursion in wild-type but not in GPR142 deficient mice in an oral glucose tolerance test (oGTT) study. These studies provide strong evidence that reduction of glucose excursion through treatment with20eis GPR142-mediated, and GPR142 agonists could be used as a potential treatment for type 2 diabetes.
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Liangqin
authors.initials: L
authors.lastname: Guo
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Dann L
authors.initials: DL
authors.lastname: Parker
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zang
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Ramzi F
authors.initials: RF
authors.lastname: Sweis
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Liu
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Sherer
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Nicole
authors.initials: N
authors.lastname: Buist
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Jenna
authors.initials: J
authors.lastname: Terebetski
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Terri
authors.initials: T
authors.lastname: Kelly
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Randal
authors.initials: R
authors.lastname: Bugianesi
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Birgit T
authors.initials: BT
authors.lastname: Priest
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Karen H
authors.initials: KH
authors.lastname: Dingley
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Li
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Stan
authors.initials: S
authors.lastname: Mitelman
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Gino
authors.initials: G
authors.lastname: Salituro
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Trujillo
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Michele
authors.initials: M
authors.lastname: Pachanski
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Melissa
authors.initials: M
authors.lastname: Kirkland
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Powles
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: George J
authors.initials: GJ
authors.lastname: Eiermann
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Yue
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Jin
authors.initials: J
authors.lastname: Shang
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Howard
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Feroze
authors.initials: F
authors.lastname: Ujjainwalla
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Sinz
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: John S
authors.initials: JS
authors.lastname: Debenham
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Edmondson
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Ravi P
authors.initials: RP
authors.lastname: Nargund
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: William K
authors.initials: WK
authors.lastname: Hagmann
authors.affiliation: Departments of Medicinal Chemistry, Discovery Pharmaceutical Sciences, Pharmacokenetics Pharmacodynamics Drug Metabolism, Diabetes Research, and Cardiometabolic Disease, Merck & Co., Inc., MRL , 126 East Lincoln Avenue, PO Box 2000, Rahway, New Jersey 07065, United States.
authors.forename: Derun
authors.initials: D
authors.lastname: Li
keywords: GPR142 agonists; glucose-stimulated insulin secretion (GSIS); solubility; triazole; type 2 diabetes mellitus (T2DM)