Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Jul 27;8(9):947-952.
doi: 10.1021/acsmedchemlett.7b00233. eCollection 2017 Sep 14.

Discovery of an Isothiazole-Based Phenylpropanoic Acid GPR120 Agonist as a Development Candidate for Type 2 Diabetes

Xuqing Zhang  1 , Chaozhong Cai  1 , Zhihua Sui  1 , Mark Macielag  1 , Yuanping Wang  1 , Wen Yan  1 , Arthur Suckow  1 , Hong Hua  1 , Austin Bell  1 , Peter Haug  1 , Wilma Clapper  1 , Celia Jenkinson  1 , Joseph Gunnet  1 , James Leonard  1 , William V Murray  1
Affiliations

Discovery of an Isothiazole-Based Phenylpropanoic Acid GPR120 Agonist as a Development Candidate for Type 2 Diabetes

Xuqing Zhang et al. ACS Med Chem Lett. .

Abstract

We have discovered a novel series of isothiazole-based phenylpropanoic acids as GPR120 agonists. Extensive structure-activity relationship studies led to the discovery of a potent GPR120 agonist 4x, which displayed good EC50 values in both calcium and β-arrestin assays. It also presented good pharmaceutical properties and a favorable PK profile. Moreover, it demonstrated in vivo antidiabetic activity in C57BL/6 DIO mice. Studies in WT and knockout DIO mice showed that it improved glucose handling during an OGTT via GPR120. Overall, 4x possessed promising antidiabetic effect and good safety profile to be a development candidate.

Keywords: GPR120; phenylpropanoic acid; type 2 diabetes.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Isothiazole-based phenylpropanoic acids.
Scheme 1
Scheme 1. Synthesis of Isothiazoles 4
Reagents and conditions: (1) chlorocarbonylsulfenyl chloride, K2CO3 reflux overnight in toluene, 75–92%; (2) R2 ≡ CO2ET, 1,3-di-Cl-benzene, 180 °C for 18 h, 80–88%; (3) DIBAL in toluene, −78 °C 1 h, 72–85%; (4) MsCl, TEA, 0 °C 1 h and then formula image, K2CO3 in DMF rt to 80 °C for 4 h–overnight, 62–81%; (5) LiOH·H2O, THF/MeOH/water (1:1:1), rt for 2 h–overnight, 85–98%.
Scheme 2
Scheme 2. Synthesis of Isothiazoles 9a and 9b
Reagents and conditions: (1) propanedinitrile, piperidine in n-butanol, rt for 16 h, 56%; (2) S2Cl2, pyridine, 145 °C for 5 h, 57%; (3) H2SO4, 135 °C for 3 h followed by NaNO2 in water, 0–50 °C for 0.5 h, 23%; (4) LAH in THF, 0 °C to r.t for 12 h, 42%; (5) MsCl, TEA 0 °C for 1 h and then ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate, K2CO3 in DMF 25 °C for 4 h, 72%; (6) H2 (1 atm), 5% Pd/C in EtOH, rt overnight, 36%; (7) LiOH.H2O, THF/MeOH/water (1:1:1), rt for 2 h, 90–95%.
Scheme 3
Scheme 3. Synthesis of Isothiazole 9c
Reagents and conditions: (1) isopentyl nitrite, Br2 in 3-methyl-1-nitrobutane 0 °C for 0.5 h, 85%; (2) H2SO4, 135 °C for 3 h followed by NaNO2 in water, 0–50 °C for 0.5 h, 75%; (3) BH3 in THF, 0 °C to rt for 12 h, 25%; (4) (4-chloro-phenyl)boronic acid, Pd(PPh3)4 (cat), K3PO4 in dioxane/water (1:1) 90 °C for 3 h, 78%; (5) ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate, n-Bu3P, ADDP in toluene 80 °C for 4 h, 70%; (6) LiOH.H2O, THF/MeOH/water (1:1:1), rt for 2 h, 88%.
Figure 2
Figure 2
Compound 4x reduces glucose excursion during OGTT in C57BL/6 DIO mice.
Figure 3
Figure 3
Compound 4x reduces glucose excursion via GPR120.
See this image and copyright information in PMC

References

    1. Hirasawa A.; Tsumaya K.; Awaji T.; Katsuma S.; Adachi T.; Yamada M.; Sugimoto Y.; Miyazaki S.; Tsujimoto G. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat. Med. 2005, 11, 90.10.1038/nm1168. - DOI - PubMed
    1. Tikhonova I. G.Application of GPCR Structures for Modelling of Free Fatty Acid Receptors. In Handbook of Experimental Pharmacology; Free Fatty Acid Receptors; Milligan G., Ikuo K., Eds.; Springer International Publishing: 2017; Vol. 236, pp 57–77. - PubMed
    1. Moore K.; Zhang Q.; Murgolo N.; Hosted T.; Duffy R. Cloning and characterization of the rat free fatty acid receptor GPR120: in vivo effect of the natural ligand on GLP-1 secretion and proliferation of pancreatic beta cells. Comp. Comp. Biochem. Physiol., Part B: Biochem. Mol. Biol. 2009, 154, 419.10.1016/j.cbpb.2009.08.005. - DOI - PubMed
    1. Vangaveti V.; Shashidhar V.; Jarrod G.; Baune B. T.; Kennedy R. L. Free fatty acid receptors: emerging targets for treatment of diabetes and its complications. Ther. Adv. Endocrinol. Metab. 2010, 1, 165.10.1177/2042018810381066. - DOI - PMC - PubMed
    1. Oh D. Y.; Talukdar S.; Bae E. J.; Imamura T.; Morinaga H.; Fan W. Q.; Li P. P.; Lu W. J.; Watkins S. M.; Olefsky J. M. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 2010, 142, 687.10.1016/j.cell.2010.07.041. - DOI - PMC - PubMed