PMID- 28105274
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20201001
IS  - 1948-5875 (Print)
IS  - 1948-5875 (Electronic)
IS  - 1948-5875 (Linking)
VI  - 8
IP  - 1
DP  - 2017 Jan 12
TI  - Design, Synthesis, and Evaluation of Novel and Selective G-protein Coupled 
      Receptor 120 (GPR120) Spirocyclic Agonists.
PG  - 49-54
LID - 10.1021/acsmedchemlett.6b00360 [doi]
AB  - Type 2 diabetes mellitus (T2DM) is an ever increasing worldwide epidemic, and the 
      identification of safe and effective insulin sensitizers, absent of weight gain, 
      has been a long-standing goal of diabetes research. G-protein coupled receptor 
      120 (GPR120) has recently emerged as a potential therapeutic target for treating 
      T2DM. Natural occurring, and more recently, synthetic agonists have been 
      associated with insulin sensitizing, anti-inflammatory, and fat metabolism 
      effects. Herein we describe the design, synthesis, and evaluation of a novel 
      spirocyclic GPR120 agonist series, which culminated in the discovery of potent 
      and selective agonist 14. Furthermore, compound 14 was evaluated in vivo and 
      demonstrated acute glucose lowering in an oral glucose tolerance test (oGTT), as 
      well as improvements in homeostatic measurement assessment of insulin resistance 
      (HOMA-IR; a surrogate marker for insulin sensitization) and an increase in 
      glucose infusion rate (GIR) during a hyperinsulinemic euglycemic clamp in 
      diet-induced obese (DIO) mice.
FAU - Cox, Jason M
AU  - Cox JM
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Chu, Hong D
AU  - Chu HD
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Chelliah, Mariappan V
AU  - Chelliah MV
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Debenham, John S
AU  - Debenham JS
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Eagen, Keith
AU  - Eagen K
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Lan, Ping
AU  - Lan P
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Lombardo, Matthew
AU  - Lombardo M
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - London, Clare
AU  - London C
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Plotkin, Michael A
AU  - Plotkin MA
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Shah, Unmesh
AU  - Shah U
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Sun, Zhongxiang
AU  - Sun Z
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Vaccaro, Henry M
AU  - Vaccaro HM
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Venkatraman, Srikanth
AU  - Venkatraman S
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Suzuki, Takao
AU  - Suzuki T
AD  - WuXi AppTec , Shanghai, 200131, China.
FAU - Wang, Nengxue
AU  - Wang N
AD  - WuXi AppTec , Shanghai, 200131, China.
FAU - Ashley, Eric R
AU  - Ashley ER
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Crespo, Alejandro
AU  - Crespo A
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Madeira, Maria
AU  - Madeira M
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Leung, Dennis H
AU  - Leung DH
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Alleyne, Candice
AU  - Alleyne C
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Ogawa, Aimie M
AU  - Ogawa AM
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Souza, Sarah
AU  - Souza S
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Thomas-Fowlkes, Brande
AU  - Thomas-Fowlkes B
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Di Salvo, Jerry
AU  - Di Salvo J
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Weinglass, Adam
AU  - Weinglass A
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Kirkland, Melissa
AU  - Kirkland M
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Pachanski, Michele
AU  - Pachanski M
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Powles, Mary Ann
AU  - Powles MA
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Tozzo, Effie
AU  - Tozzo E
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Akiyama, Taro E
AU  - Akiyama TE
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Ujjainwalla, Feroze
AU  - Ujjainwalla F
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Tata, James R
AU  - Tata JR
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
FAU - Sinz, Christopher J
AU  - Sinz CJ
AD  - Merck & Co., Inc., Kenilworth, New Jersey 07033, United States; Merck & Co., 
      Inc., Rahway, New Jersey 07065, United States.
LA  - eng
PT  - Journal Article
DEP - 20161117
PL  - United States
TA  - ACS Med Chem Lett
JT  - ACS medicinal chemistry letters
JID - 101521073
PMC - PMC5238469
OTO - NOTNLM
OT  - FFAR4
OT  - GPR120
OT  - insulin sensitization
OT  - spirocyclic
OT  - type 2 diabetes
COIS- The authors declare no competing financial interest.
EDAT- 2017/01/21 06:00
MHDA- 2017/01/21 06:01
PMCR- 2018/01/12
CRDT- 2017/01/21 06:00
PHST- 2016/09/12 00:00 [received]
PHST- 2016/11/17 00:00 [accepted]
PHST- 2017/01/21 06:00 [entrez]
PHST- 2017/01/21 06:00 [pubmed]
PHST- 2017/01/21 06:01 [medline]
PHST- 2018/01/12 00:00 [pmc-release]
AID - 10.1021/acsmedchemlett.6b00360 [doi]
PST - epublish
SO  - ACS Med Chem Lett. 2016 Nov 17;8(1):49-54. doi: 10.1021/acsmedchemlett.6b00360. 
      eCollection 2017 Jan 12.