PMID- 27994747
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200930
IS  - 1948-5875 (Print)
IS  - 1948-5875 (Electronic)
IS  - 1948-5875 (Linking)
VI  - 7
IP  - 12
DP  - 2016 Dec 8
TI  - Discovery and Optimization of a Novel Triazole Series of GPR142 Agonists for the 
      Treatment of Type 2 Diabetes.
PG  - 1107-1111
AB  - 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 compound 4 suffered from poor metabolic stability and poor solubility. Lead 
      optimization strategies to improve potency, efficacy, metabolic stability, and 
      solubility are described. This optimization led to compound 20e, 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 
      with 20e is GPR142-mediated, and GPR142 agonists could be used as a potential 
      treatment for type 2 diabetes.
FAU - Guo, Liangqin
AU  - Guo L
AD  - 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.
FAU - Parker, Dann L
AU  - Parker DL
AD  - 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.
FAU - Zang, Yi
AU  - Zang Y
AD  - 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.
FAU - Sweis, Ramzi F
AU  - Sweis RF
AD  - 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.
FAU - Liu, Weiguo
AU  - Liu W
AD  - 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.
FAU - Sherer, Edward C
AU  - Sherer EC
AD  - 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.
FAU - Buist, Nicole
AU  - Buist N
AD  - 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.
FAU - Terebetski, Jenna
AU  - Terebetski J
AD  - 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.
FAU - Kelly, Terri
AU  - Kelly T
AD  - 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.
FAU - Bugianesi, Randal
AU  - Bugianesi R
AD  - 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.
FAU - Priest, Birgit T
AU  - Priest BT
AD  - 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.
FAU - Dingley, Karen H
AU  - Dingley KH
AD  - 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.
FAU - Li, Xiaofang
AU  - Li X
AD  - 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.
FAU - Mitelman, Stan
AU  - Mitelman S
AD  - 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.
FAU - Salituro, Gino
AU  - Salituro G
AD  - 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.
FAU - Trujillo, Maria E
AU  - Trujillo ME
AD  - 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.
FAU - Pachanski, Michele
AU  - Pachanski M
AD  - 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.
FAU - Kirkland, Melissa
AU  - Kirkland M
AD  - 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.
FAU - Powles, Mary Ann
AU  - Powles MA
AD  - 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.
FAU - Eiermann, George J
AU  - Eiermann GJ
AD  - 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.
FAU - Feng, Yue
AU  - Feng Y
AD  - 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.
FAU - Shang, Jin
AU  - Shang J
AD  - 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.
FAU - Howard, Andrew D
AU  - Howard AD
AD  - 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.
FAU - Ujjainwalla, Feroze
AU  - Ujjainwalla F
AD  - 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.
FAU - Sinz, Christopher J
AU  - Sinz CJ
AD  - 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.
FAU - Debenham, John S
AU  - Debenham JS
AD  - 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.
FAU - Edmondson, Scott D
AU  - Edmondson SD
AD  - 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.
FAU - Nargund, Ravi P
AU  - Nargund RP
AD  - 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.
FAU - Hagmann, William K
AU  - Hagmann WK
AD  - 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.
FAU - Li, Derun
AU  - Li D
AD  - 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.
LA  - eng
PT  - Journal Article
DEP - 20161012
PL  - United States
TA  - ACS Med Chem Lett
JT  - ACS medicinal chemistry letters
JID - 101521073
PMC - PMC5150677
OTO - NOTNLM
OT  - GPR142 agonists
OT  - glucose-stimulated insulin secretion (GSIS)
OT  - solubility
OT  - triazole
OT  - type 2 diabetes mellitus (T2DM)
COIS- The authors declare no competing financial interest.
EDAT- 2016/12/21 06:00
MHDA- 2016/12/21 06:01
PMCR- 2017/12/08
CRDT- 2016/12/21 06:00
PHST- 2016/08/10 00:00 [received]
PHST- 2016/10/06 00:00 [accepted]
PHST- 2016/12/21 06:00 [entrez]
PHST- 2016/12/21 06:00 [pubmed]
PHST- 2016/12/21 06:01 [medline]
PHST- 2017/12/08 00:00 [pmc-release]
AID - 10.1021/acsmedchemlett.6b00314 [doi]
PST - epublish
SO  - ACS Med Chem Lett. 2016 Oct 12;7(12):1107-1111. doi: 
      10.1021/acsmedchemlett.6b00314. eCollection 2016 Dec 8.