Design of Potent and Orally Active GPR119 Agonists for the Treatment of Type II Diabetes.
We report herein the design and synthesis of a series of potent and selective GPR119 agonists. Our objective was to develop a GPR119 agonist with properties that were suitable for fixed-dose combination with a DPP4 inhibitor. Starting from a phenoxy analogue (1), medicinal chemistry efforts directed toward reducing half-life and increasing solubility led to the synthesis of a series of benzyloxy analogues. Compound 28 was chosen for further profiling because of its favorable physicochemical properties and excellent GPR119 potency across species. This compound exhibited a clean off-target profile in counterscreens and good in vivo efficacy in mouse oGTT.
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Ping
P
Liu
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Zhiyong
Z
Hu
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Byron G
BG
DuBois
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Christopher R
CR
Moyes
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
David N
DN
Hunter
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Cheng
C
Zhu
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Nam Fung
NF
Kar
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Yuping
Y
Zhu
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Joie
J
Garfunkle
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Ling
L
Kang
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Gary
G
Chicchi
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Anka
A
Ehrhardt
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Andrea
A
Woods
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Toru
T
Seo
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Morgan
M
Woods
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Margaret
M
van Heek
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Karen H
KH
Dingley
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Jianmei
J
Pang
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Gino M
GM
Salituro
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Joyce
J
Powell
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Jenna L
JL
Terebetski
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Viktor
V
Hornak
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Louis-Charles
LC
Campeau
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Joe
J
Lamberson
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Fez
F
Ujjainwalla
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Michael
M
Miller
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Andrew
A
Stamford
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Harold B
HB
Wood
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Timothy
T
Kowalski
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Ravi P
RP
Nargund
Departments of Medicinal Chemistry, Diabetes Biology, Pharmacology, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Basic Pharmaceutical Sciences, Chemical Modeling and Informatics, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Scott D
SD
Edmondson
GPR119 agonists; Type II diabetes; benzyloxy analogues; chiral cis-cyclopropanes; oGTT