PMID- 28277660
OWN - NLM
STAT- MEDLINE
DCOM- 20170424
LR  - 20181222
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 60
IP  - 7
DP  - 2017 Apr 13
TI  - Discovery of Potent and Orally Bioavailable GPR40 Full Agonists Bearing 
      Thiophen-2-ylpropanoic Acid Scaffold.
PG  - 2697-2717
LID - 10.1021/acs.jmedchem.6b01357 [doi]
AB  - The free fatty acid receptor GPR40 is predominantly expressed in pancreatic 
      beta-cells and enhances insulin secretion in a glucose dependent manner. Therefore, 
      GPR40 agonists are possible novel insulin secretagogues with reduced or no risk 
      of hypoglycemia for the treatment of type 2 diabetes mellitus (T2DM). Chemically 
      and structurally diverse GPR40 agonists with high safety are pursued for the 
      clinical development of GPR40-based pharmacotherapeutics. Herein we report our 
      design and discovery of a new chemotype of GPR40 agonists free of the typical 
      phenylpropanoic acid scaffold. The thiophen-2-ylpropanoic acid containing GPR40 
      modulators functioned as full agonists with high-efficacy response (E(max)) and 
      reduced lipophilicity. Significantly, the lead compound in this series, (R)-7k, 
      exhibited more potent in vitro glucose-stimulated insulin secretion and in vivo 
      glucose-lowering effects (10 mg/kg, po) than the GPR40 partial agonist TAK-875, 
      which was once in phase III clinical trials, and high selectivity over the 
      relevant receptors GPR120 and PPARgamma.
FAU - Li, He
AU  - Li H
AD  - CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.
AD  - University of Chinese Academy of Sciences , Beijing 100049, China.
FAU - Huang, Qi
AU  - Huang Q
AD  - CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.
AD  - University of Chinese Academy of Sciences , Beijing 100049, China.
FAU - Chen, Cheng
AU  - Chen C
AD  - CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.
AD  - Department of Chemistry, Shanghai University , 99 Shangda Road, Shanghai 200444, 
      China.
FAU - Xu, Bin
AU  - Xu B
AUID- ORCID: 0000-0002-9251-6930
AD  - Department of Chemistry, Shanghai University , 99 Shangda Road, Shanghai 200444, 
      China.
FAU - Wang, He-Yao
AU  - Wang HY
AD  - CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.
FAU - Long, Ya-Qiu
AU  - Long YQ
AUID- ORCID: 0000-0002-9209-0503
AD  - CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai 201203, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170317
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Benzofurans)
RN  - 0 (Blood Glucose)
RN  - 0 (FFAR1 protein, human)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Insulin)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 0 (Sulfones)
RN  - 0 (TAK-875)
RN  - 0 (Thiophenes)
SB  - IM
MH  - Administration, Oral
MH  - Animals
MH  - Benzofurans/pharmacology
MH  - Blood Glucose/metabolism
MH  - CHO Cells
MH  - Cell Line
MH  - Cricetulus
MH  - Diabetes Mellitus, Type 2/drug therapy/metabolism
MH  - Glucose Tolerance Test
MH  - Humans
MH  - Hypoglycemic Agents/administration & dosage/blood/*chemistry/*pharmacology
MH  - Insulin/metabolism
MH  - Male
MH  - Mice, Inbred ICR
MH  - Rats, Sprague-Dawley
MH  - Receptors, G-Protein-Coupled/*agonists/metabolism
MH  - Sulfones/pharmacology
MH  - Thiophenes/administration & dosage/blood/*chemistry/*pharmacology
EDAT- 2017/03/10 06:00
MHDA- 2017/04/25 06:00
CRDT- 2017/03/10 06:00
PHST- 2017/03/10 06:00 [pubmed]
PHST- 2017/04/25 06:00 [medline]
PHST- 2017/03/10 06:00 [entrez]
AID - 10.1021/acs.jmedchem.6b01357 [doi]
PST - ppublish
SO  - J Med Chem. 2017 Apr 13;60(7):2697-2717. doi: 10.1021/acs.jmedchem.6b01357. Epub 
      2017 Mar 17.