PMID- 35051813
OWN - NLM
STAT- MEDLINE
DCOM- 20220307
LR  - 20220307
IS  - 1464-3391 (Electronic)
IS  - 0968-0896 (Linking)
VI  - 56
DP  - 2022 Feb 15
TI  - Design, synthesis, and biological evaluation of novel dual FFA1 and PPARdelta 
      agonists possessing phenoxyacetic acid scaffold.
PG  - 116615
LID - S0968-0896(22)00007-4 [pii]
LID - 10.1016/j.bmc.2022.116615 [doi]
AB  - The free fatty acid receptor 1 (FFA1/GPR40) and peroxisome proliferator-activated 
      receptor delta (PPARdelta) have been widely considered as promising targets for type 2 
      diabetes mellitus (T2DM) due to their respective roles in promoting insulin 
      secretion and improving insulin sensitivity. Hence, the dual FFA1/PPARdelta agonists 
      may exert synergistic effects by simultaneously activating FFA1 and PPARdelta. The 
      present study performed systematic exploration around previously reported FFA1 
      agonist 
      2-(2-fluoro-4-((2'-methyl-4'-(3-(methylsulfonyl)propoxy)-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)acetic 
      acid (lead compound), leading to the identification of a novel dual FFA1/PPARdelta 
      agonist 2-(2-fluoro-4-((3-(6-methoxynaphthalen-2-yl)benzyl)oxy)phenoxy)acetic 
      acid (the optimal compound), which displayed high selectivity over PPARalpha and 
      PPARgamma. In addition, the docking study provided us with detailed binding modes of 
      the optimal compound in FFA1 and PPARdelta. Furthermore, the optimal compound 
      exhibited greater glucose-lowering effects than lead compound, which might 
      attribute to its synergistic effects by simultaneously modulating insulin 
      secretion and resistance. Moreover, the optimal compound has an acceptable safety 
      profile in the acute toxicity study at a high dose of 500 mg/kg Therefore, our 
      results provided a novel dual FFA1/PPARdelta agonist with excellent glucose-lowering 
      effects in vivo.
CI  - Copyright (c) 2022 Elsevier Ltd. All rights reserved.
FAU - Zhou, Zongtao
AU  - Zhou Z
AD  - School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR 
      China; Key Laboratory of New Drug Discovery and Evaluation, Guangdong 
      Pharmaceutical University, Guangzhou 510006, PR China; Guangzhou Key Laboratory 
      of Construction and Application of New Drug Screening Model Systems, Guangdong 
      Pharmaceutical University, Guangzhou 510006, PR China.
FAU - Cai, Zongyu
AU  - Cai Z
AD  - School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR 
      China.
FAU - Zhang, Congzi
AU  - Zhang C
AD  - Xianning Central Hospital, The First Affiliated Hospital of Hubei University Of 
      Science And Technology, Xianning 437000, PR China.
FAU - Yang, Benhui
AU  - Yang B
AD  - School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR 
      China.
FAU - Chen, Lianru
AU  - Chen L
AD  - School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR 
      China.
FAU - He, Yepu
AU  - He Y
AD  - Xianning Central Hospital, The First Affiliated Hospital of Hubei University Of 
      Science And Technology, Xianning 437000, PR China.
FAU - Zhang, Luyong
AU  - Zhang L
AD  - School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR 
      China; Key Laboratory of New Drug Discovery and Evaluation, Guangdong 
      Pharmaceutical University, Guangzhou 510006, PR China; Guangzhou Key Laboratory 
      of Construction and Application of New Drug Screening Model Systems, Guangdong 
      Pharmaceutical University, Guangzhou 510006, PR China; Jiangsu Key Laboratory of 
      Drug Screening, China Pharmaceutical University, Nanjing 210009, PR China. 
      Electronic address: lyzhang@cpu.edu.cn.
FAU - Li, Zheng
AU  - Li Z
AD  - School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR 
      China; Key Laboratory of New Drug Discovery and Evaluation, Guangdong 
      Pharmaceutical University, Guangzhou 510006, PR China; National Key Clinical 
      Department (Clinical Pharmacy), The First Affiliated Hospital of Guangdong 
      Pharmaceutical University, Guangzhou 510006, PR China. Electronic address: 
      li.zheng.sky@163.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220115
PL  - England
TA  - Bioorg Med Chem
JT  - Bioorganic & medicinal chemistry
JID - 9413298
RN  - 0 (Acetates)
RN  - 0 (FFAR1 protein, human)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (PPAR delta)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - YRC253429Q (phenoxyacetic acid)
SB  - IM
MH  - Acetates/chemical synthesis/chemistry/*pharmacology
MH  - Animals
MH  - Dose-Response Relationship, Drug
MH  - *Drug Design
MH  - Humans
MH  - Hypoglycemic Agents/chemical synthesis/chemistry/*pharmacology
MH  - Male
MH  - Mice
MH  - Mice, Inbred ICR
MH  - Molecular Docking Simulation
MH  - Molecular Structure
MH  - PPAR delta/*agonists
MH  - Receptors, G-Protein-Coupled/*agonists
MH  - Structure-Activity Relationship
OTO - NOTNLM
OT  - Dual agonist
OT  - FFA1
OT  - Glucose-lowering
OT  - PPARdelta
OT  - T2DM
EDAT- 2022/01/21 06:00
MHDA- 2022/03/08 06:00
CRDT- 2022/01/20 20:25
PHST- 2021/10/14 00:00 [received]
PHST- 2021/12/24 00:00 [revised]
PHST- 2022/01/06 00:00 [accepted]
PHST- 2022/01/21 06:00 [pubmed]
PHST- 2022/03/08 06:00 [medline]
PHST- 2022/01/20 20:25 [entrez]
AID - S0968-0896(22)00007-4 [pii]
AID - 10.1016/j.bmc.2022.116615 [doi]
PST - ppublish
SO  - Bioorg Med Chem. 2022 Feb 15;56:116615. doi: 10.1016/j.bmc.2022.116615. Epub 2022 
      Jan 15.