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Current Medicinal Chemistry

Author(s): Dapinder Pal Singh Loona, Bhanuranjan Das, Ramandeep Kaur, Rajnish Kumar and Ashok Kumar Yadav*

DOI: 10.2174/0929867329666220927113614

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Free Fatty Acid Receptors (FFARs): Emerging Therapeutic Targets for the Management of Diabetes Mellitus

Page: [3404 - 3440] Pages: 37

  • * (Excluding Mailing and Handling)

Abstract

Free fatty acids (FFAs) present in our dietary fats not only act as vital nutrients but also function as signalling molecules and modulate key biological functions through their active involvement in a multitude of energy metabolism pathways. However, it has been reported that excessive intake of dietary fat contributes to the development of different types of Diabetes mellitus. Free fatty acid receptors are the key regulators of most metabolic disorders. Among them, diabetes mellitus is a severe growing disorder and found in every corner of the world. For various metabolic disorders, particularly type 2 diabetes mellitus, these different free fatty acid receptors are being explored as drug targets. In the present review, various FFAs sensing G-protein coupled receptors (GPR) like GPR40 (FFAR1), GPR43 (FFAR2), GPR41 (FFAR3), GPR120 (FFAR4), and GPR84 are being explored as emerging novel therapeutic targets for antidiabetic drugs. Additionally, this review has covered pre-clinical discovery and development of different selective ligands targeted to these receptors starting from hit identification to lead optimization via chemical modification and the challenges and tactics selected by different medicinal chemists to improve potency, physicochemical properties, safety profiles, and pharmacokinetics of different FFAR agonists for making a potential drug candidate. Several molecules have been withdrawn in the clinical trials without reporting any reasons. We believe that this review will help the researchers to find a new direction in the discovery of new antidiabetic drugs.

Keywords: Diabetes Mellitus, Free Fatty acids, G-protein coupled receptors, FFAR1, FFAR2, FFAR3, FDAR4

[1]
Daclich, K.A. Diabetes mellitus: A guide to patient care; Lippincott Williams & Wilkins: Pennsylvania, USA, 2007.
[2]
Safavi, M.; Foroumadi, A.; Abdollahi, M. The importance of synthetic drugs for type 2 diabetes drug discovery. Expert Opin. Drug Discov., 2013, 8(11), 1339-1363.
[http://dx.doi.org/10.1517/17460441.2013.837883] [PMID: 24050217]
[3]
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care, 2010, 33(Suppl. 1), S62-S69.
[http://dx.doi.org/10.2337/dc10-S062]
[4]
International Diabetes Federation. Diabetes atlas, 2nd ed.; Brussels: Belgium, 2003.
[5]
Kavitha, N.; De, S.; Kanagasabai, S. Oral hypoglycemic agents in pregnancy: An update. J. Obstet. Gynaecol. India, 2013, 63(2), 82-87.
[http://dx.doi.org/10.1007/s13224-012-0312-z] [PMID: 24431611]
[6]
Marín-Peñalver, J.J.; Martín-Timón, I.; Sevillano-Collantes, C.; Cañizo-Gómez, F.J. Update on the treatment of type 2 diabetes mellitus. World J. Diabetes, 2016, 7(17), 354-395.
[http://dx.doi.org/10.4239/wjd.v7.i17.354] [PMID: 27660695]
[7]
Offermanns, S. Free fatty acid receptors. In: Encyclopaedia of Molecular Pharmacology; Offermanns, S.; Rosenthal, W., Eds.; Springer: Cham, 2020.
[http://dx.doi.org/10.1007/978-3-030-21573-6_10035-1]
[8]
Kimura, I.; Ichimura, A.; Ohue-Kitano, R.; Igarashi, M. Free fatty acid receptors in health and disease. Am. Physiol. Soc. J., 2018, 100(1), 171-210.
[9]
Hara, T.; Hirasawa, A.; Ichimura, A.; Kimura, I.; Tsujimoto, G. Free fatty acid receptors FFAR1 and GPR120 as novel therapeutic targets for metabolic disorders. J. Pharm. Sci., 100(9), 3594-3601.
[10]
Kimura, I.; Ichimura, A.; Ohue-Kitano, R.; Igarashi, M. Free fatty acid receptors in health and disease. Physiol. Rev., 2020, 100(1), 171-210.
[http://dx.doi.org/10.1152/physrev.00041.2018] [PMID: 31487233]
[11]
Edfalk, S.; Steneberg, P.; Edlund, H. Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion. Diabetes, 2008, 57(9), 2280-2287.
[http://dx.doi.org/10.2337/db08-0307] [PMID: 18519800]
[12]
Watterson, K.R.; Hudson, B.D.; Ulven, T.; Milligan, G. Treatment of type 2 diabetes by free Fatty Acid receptor agonists. Front. Endocrinol. (Lausanne), 2014, 5, 137.
[http://dx.doi.org/10.3389/fendo.2014.00137] [PMID: 25221541]
[13]
(a) Kristinsson, H.; Smith, D.M.; Bergsten, P.; Sargsyan, E. FFAR1 is involved in both the acute and chronic effects of palmitate on insulin secretion. Endocrinology, 2009, 154(11), 4078-4088.
[http://dx.doi.org/10.1210/en.2013-1352];
(b) Nagasumi, K.; Esaki, R.; Iwachidow, K.; Yasuhara, Y.; Ogi, K.; Tanaka, H.; Nakata, M.; Yano, T.; Shimakawa, K.; Taketomi, S.; Takeuchi, K.; Odaka, H.; Kaisho, Y. Overexpression of GPR40 in pancreatic β-cells augments glucose-stimulated insulin secretion and improves glucose tolerance in normal and diabetic mice. Diabetes, 2009, 58(5), 1067-1076.
[http://dx.doi.org/10.2337/db08-1233]
[14]
(a) Milligan, G.; Shimpukade, B.; Ulven, T.; D Hudson, B. Complex pharmacology of free fatty acid receptors. Chem. Rev., 2020, 117(1), 67-110.
[http://dx.doi.org/10.1021/acs.chemrev.6b00056];
(b) Li, Z.; Zhou, Z.; Zhang, L. Current status of GPR40/FFAR1 modulators in medicinal chemistry (2016-2019): A patent review. Expert Opin. Ther. Patents, 2020, 30, 27-38.
[http://dx.doi.org/10.1080/13543776.2020.1698546];
(c) Li, Z.; Xu, X.; Huang, W.; Qian, H. Free fatty acid receptor 1 (FFAR1) as an emerging therapeutic target for type 2 diabetes mellitus: Recent progress and prevailing challenges. Med. Res. Rev., 2018, 38(2), 381-425.
[http://dx.doi.org/10.1002/med.21441];
d) Chen, C.; Li, H.; Long, Y.-Q. GPR40 agonists for the treatment of type 2 diabetes mellitus: The biological characteristics and the chemical space. Bioorg. Med. Chem. Lett., 2016, 26, 5603-5612.
[http://dx.doi.org/10.1016/j.bmcl.2016.10.074]
[15]
Briscoe, C.P.; Peat, A.J.; McKeown, S.C.; Corbett, D.F.; Goetz, A.S.; Littleton, T.R.; McCoy, D.C.; Kenakin, T.P.; Andrews, J.L.; Ammala, C.; Fornwald, J.A.; Ignar, D.M.; Jenkinson, S. Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: Identification of agonist and antagonist small molecules. Br. J. Pharmacol., 2006, 148(5), 619-628.
[http://dx.doi.org/10.1038/sj.bjp.0706770] [PMID: 16702987]
[16]
Christiansen, E.; Urban, C.; Merten, N.; Liebscher, K.; Karlsen, K.K.; Hamacher, A.; Spinrath, A.; Bond, A.D.; Drewke, C.; Ullrich, S.; Kassack, M.U.; Kostenis, E.; Ulven, T. Discovery of potent and selective agonists for the free fatty acid receptor 1 (FFA(1)/GPR40), a potential target for the treatment of type II diabetes. J. Med. Chem., 2008, 51(22), 7061-7064.
[http://dx.doi.org/10.1021/jm8010178] [PMID: 18947221]
[17]
Bharate, S.B.; Rodge, A.; Joshi, R.K.; Kaur, J.; Srinivasan, S.; Senthil Kumar, S.; Kulkarni-Almeida, A.; Balachandran, S.; Balakrish-nan, A.; Vishwakarma, R.A. Discovery of diacylphloroglucinols as a new class of GPR40 (FFAR1) agonists. Bioorg. Med. Chem. Lett., 2008, 18(24), 6357-6361.
[http://dx.doi.org/10.1016/j.bmcl.2008.10.085] [PMID: 18993064]
[18]
Negoro, N.; Sasaki, S.; Mikami, S.; Ito, M.; Suzuki, M.; Tsujihata, Y.; Ito, R.; Harada, A.; Takeuchi, K.; Suzuki, N.; Miyazaki, J.; Santou, T.; Odani, T.; Kanzaki, N.; Funami, M.; Tanaka, T.; Kogame, A.; Matsunaga, S.; Yasuma, T.; Momose, Y. Discovery of TAK-875: A potent, selective, and orally bioavailable GPR40 agonist. ACS Med. Chem. Lett., 2010, 1(6), 290-294.
[http://dx.doi.org/10.1021/ml1000855] [PMID: 24900210]
[19]
Li, Z.; Qiu, Q.; Geng, X.; Yang, J.; Huang, W.; Qian, H. Free fatty acid receptor agonists for the treatment of type 2 diabetes: Drugs in preclinical to phase II clinical development. Expert Opin. Investig. Drugs, 2016, 25(8), 871-890.
[http://dx.doi.org/10.1080/13543784.2016.1189530] [PMID: 27171154]
[20]
Houze, J.B.; Zhu, L.; Sun, Y.; Akerman, M.; Qiu, W.; Zhang, A.J.; Sharma, R.; Schmitt, M.; Wang, Y.; Liu, J.; Liu, J.; Medina, J.C.; Reagan, J.D.; Luo, J.; Tonn, G.; Zhang, J.; Lu, J.Y.L.; Chen, M.; Lopez, E.; Nguyen, K.; Yang, L.; Tang, L.; Tian, H.; Shuttleworth, S.J.; Lin, D.C.H. AMG 837: A potent, orally bioavailable GPR40 agonist. Bioorg. Med. Chem. Lett., 2012, 22(2), 1267-1270.
[http://dx.doi.org/10.1016/j.bmcl.2011.10.118] [PMID: 22217876]
[21]
Sasaki, S.; Kitamura, S.; Negoro, N.; Suzuki, M.; Tsujihata, Y.; Suzuki, N.; Santou, T.; Kanzaki, N.; Harada, M.; Tanaka, Y.; Kobayashi, M.; Tada, N.; Funami, M.; Tanaka, T.; Yamamoto, Y.; Fukatsu, K.; Yasuma, T.; Momose, Y. Design, synthesis, and biological activity of potent and orally available G protein-coupled receptor 40 agonists. J. Med. Chem., 2011, 54(5), 1365-1378.
[http://dx.doi.org/10.1021/jm101405t] [PMID: 21319751]
[22]
Christiansen, E.; Due-Hansen, M.E.; Urban, C.; Grundmann, M.; Schmidt, J.; Hansen, S.V.F.; Hudson, B.D.; Zaibi, M.; Markussen, S.B.; Hagesaether, E.; Milligan, G.; Cawthorne, M.A.; Kostenis, E.; Kassack, M.U.; Ulven, T. Discovery of a potent and selective free fatty acid receptor 1 agonist with low lipophilicity and high oral bioavailability. J. Med. Chem., 2013, 56(3), 982-992.
[http://dx.doi.org/10.1021/jm301470a] [PMID: 23294321]
[23]
Wang, X.; Zhao, T.; Yang, B.; Li, Z.; Cui, J.; Dai, Y.; Qiu, Q.; Qiang, H.; Huang, W.; Qian, H. Synthesis and biological evaluation of phenoxyacetic acid derivatives as novel free fatty acid receptor 1 agonists. Bioorg. Med. Chem., 2015, 23(1), 132-140.
[http://dx.doi.org/10.1016/j.bmc.2014.11.016] [PMID: 25481394]
[24]
Zahanich, I.; Kondratov, I.; Naumchyk, V.; Kheylik, Y.; Platonov, M.; Zozulya, S.; Krasavin, M. Phenoxymethyl 1,3-oxazoles and 1,2,4-oxadiazoles as potent and selective agonists of free fatty acid receptor 1 (GPR40). Bioorg. Med. Chem. Lett., 2015, 25(16), 3105-3111.
[http://dx.doi.org/10.1016/j.bmcl.2015.06.018] [PMID: 26096679]
[25]
Li, Z.; Wang, X.; Xu, X.; Yang, J.; Qiu, Q.; Qiang, H.; Huang, W.; Qian, H. Design, synthesis and structure–activity relationship studies of novel phenoxyacetamide-based free fatty acid receptor 1 agonists for the treatment of type 2 diabetes. Bioorg. Med. Chem., 2015, 23(20), 6666-6672.
[http://dx.doi.org/10.1016/j.bmc.2015.09.010] [PMID: 26420383]
[26]
Li, Z.; Wang, X.; Xu, X.; Yang, J.; Xia, W.; Zhou, X.; Huang, W.; Qian, H. Design, synthesis and biological activity of phenoxyacetic acid derivatives as novel free fatty acid receptor 1 agonists. Bioorg. Med. Chem., 2015, 23(22), 7158-7164.
[http://dx.doi.org/10.1016/j.bmc.2015.10.011] [PMID: 26482570]
[27]
Hansen, S.V.F.; Christiansen, E.; Urban, C.; Hudson, B.D.; Stocker, C.J.; Due-Hansen, M.E.; Wargent, E.T.; Shimpukade, B.; Almeida, R.; Ejsing, C.S.; Cawthorne, M.A.; Kassack, M.U.; Milligan, G.; Ulven, T. Discovery of a potent free fatty acid 1 receptor agonist with low lipophilicity, low polar surface area, and robust in vivo efficacy. J. Med. Chem., 2016, 59(6), 2841-2846.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01962] [PMID: 26928019]
[28]
Li, Z.; Yang, J.; Gu, W.; Cao, G.; Fu, X.; Sun, X.; Zhang, Y.; Jin, H.; Huang, W.; Qian, H. Discovery of a novel oxime ether scaffold as potent and orally bioavailable free fatty acid receptor 1 agonists. RSC Advances, 2016, 6(52), 46356-46365.
[http://dx.doi.org/10.1039/C6RA07356E]
[29]
Li, Z.; Pan, M.; Su, X.; Dai, Y.; Fu, M.; Cai, X.; Shi, W.; Huang, W.; Qian, H. Discovery of novel pyrrole-based scaffold as potent and orally bioavailable free fatty acid receptor 1 agonists for the treatment of type 2 diabetes. Bioorg. Med. Chem., 2016, 24(9), 1981-1987.
[http://dx.doi.org/10.1016/j.bmc.2016.03.014] [PMID: 27020683]
[30]
Li, Z.; Qiu, Q.; Xu, X.; Wang, X.; Jiao, L.; Su, X.; Pan, M.; Huang, W.; Qian, H. Design, synthesis and Structure–activity relationship studies of new thiazole-based free fatty acid receptor 1 agonists for the treatment of type 2 diabetes. Eur. J. Med. Chem., 2016, 113, 246-257.
[http://dx.doi.org/10.1016/j.ejmech.2016.02.040] [PMID: 26945112]
[31]
Krasavin, M.; Lukin, A.; Zhurilo, N.; Kovalenko, A.; Zahanich, I.; Zozulya, S.; Moore, D.; Tikhonova, I.G. Novel free fatty acid receptor 1 (GPR40) agonists based on 1,3,4-thiadiazole-2-carboxamide scaffold. Bioorg. Med. Chem., 2016, 24(13), 2954-2963.
[http://dx.doi.org/10.1016/j.bmc.2016.04.065] [PMID: 27229618]
[32]
Li, Z.; Yang, J.; Wang, X.; Li, H.; Liu, C.; Wang, N.; Huang, W.; Qian, H. Discovery of novel free fatty acid receptor 1 agonists bearing triazole core via click chemistry. Bioorg. Med. Chem., 2016, 24(21), 5449-5454.
[http://dx.doi.org/10.1016/j.bmc.2016.08.068] [PMID: 27624524]
[33]
Hamdouchi, C.; Kahl, S.D.; Patel Lewis, A.; Cardona, G.R.; Zink, R.W.; Chen, K.; Eessalu, T.E.; Ficorilli, J.V.; Marcelo, M.C.; Otto, K.A.; Wilbur, K.L.; Lineswala, J.P.; Piper, J.L.; Coffey, D.S.; Sweetana, S.A.; Haas, J.V.; Brooks, D.A.; Pratt, E.J.; Belin, R.M.; Deeg, M.A.; Ma, X.; Cannady, E.A.; Johnson, J.T.; Yumibe, N.P.; Chen, Q.; Maiti, P.; Montrose-Rafizadeh, C.; Chen, Y.; Reifel Miller, A. The discovery, preclinical, and early clinical development of potent and selective GPR40 agonists for the treatment of type 2 diabetes mellitus (LY2881835, LY2922083, and LY2922470). J. Med. Chem., 2016, 59(24), 10891-10916.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00892] [PMID: 27749056]
[34]
Krasavin, M.; Lukin, A.; Bagnyukova, D.; Zhurilo, N.; Golovanov, A.; Zozulya, S.; Zahanich, I.; Moore, D.; Tikhonova, I.G. Polar aromatic periphery increases agonist potency of spirocyclic free fatty acid receptor (GPR40) agonists inspired by LY2881835. Eur. J. Med. Chem., 2017, 127, 357-368.
[http://dx.doi.org/10.1016/j.ejmech.2017.01.005] [PMID: 28076825]
[35]
Yang, J.; Li, Z.; Li, H.; Liu, C.; Wang, N.; Shi, W.; Liao, C.; Cai, X.; Huang, W.; Qian, H. Design, synthesis and structure–activity relationship studies of novel free fatty acid receptor 1 agonists bearing amide linker. Bioorg. Med. Chem., 2017, 25(8), 2445-2450.
[http://dx.doi.org/10.1016/j.bmc.2017.03.001] [PMID: 28285923]
[36]
Tikhonova, I.G.; Sum, C.S.; Neumann, S.; Engel, S.; Raaka, B.M.; Costanzi, S.; Gershengorn, M.C. Discovery of novel agonists and antagonists of the free fatty acid receptor 1 (FFAR1) using virtual screening. J. Med. Chem., 2008, 51(3), 625-633.
[http://dx.doi.org/10.1021/jm7012425] [PMID: 18193825]
[37]
Krasavin, M.; Lukin, A.; Bakholdina, A.; Zhurilo, N.; Onopchenko, O.; Borysko, P.; Zozulya, S.; Moore, D.; Tikhonova, I.G. Continued SAR exploration of 1,2,4-thiadiazole-containing scaffolds in the design of free fatty acid receptor 1 (GPR40) agonists. Eur. J. Med. Chem., 2017, 140, 229-238.
[http://dx.doi.org/10.1016/j.ejmech.2017.09.019] [PMID: 28938138]
[38]
Li, Z.; Liu, C.; Xu, X.; Qiu, Q.; Su, X.; Dai, Y.; Yang, J.; Li, H.; Shi, W.; Liao, C.; Pan, M.; Huang, W.; Qian, H. Discovery of phenylsulfonyl acetic acid derivatives with improved efficacy and safety as potent free fatty acid receptor 1 agonists for the treatment of type 2 diabetes. Eur. J. Med. Chem., 2017, 138, 458-479.
[http://dx.doi.org/10.1016/j.ejmech.2017.07.001] [PMID: 28689096]
[39]
Li, Z.; Liu, C.; Shi, W.; Cai, X.; Dai, Y.; Liao, C.; Huang, W.; Qian, H. Identification of highly potent and orally available free fatty acid receptor 1 agonists bearing isoxazole scaffold. Bioorg. Med. Chem., 2018, 26(3), 703-711.
[http://dx.doi.org/10.1016/j.bmc.2017.12.030] [PMID: 29291938]
[40]
Li, Z.; Xu, X.; Hou, J.; Wang, S.; Jiang, H.; Zhang, L. Structure-based optimization of free fatty acid receptor 1 agonists bearing thiazole scaffold. Bioorg. Chem., 2018, 77, 429-435.
[http://dx.doi.org/10.1016/j.bioorg.2018.01.039] [PMID: 29433092]
[41]
Li, Z.; Liu, C.; Xu, X.; Shi, W.; Li, H.; Dai, Y.; Cai, X.; Huang, W.; Qian, H. Design, synthesis, and biological evaluation of deuterated phenylpropionic acid derivatives as potent and long-acting free fatty acid receptor 1 agonists. Bioorg. Chem., 2018, 76, 303-313.
[http://dx.doi.org/10.1016/j.bioorg.2017.12.012] [PMID: 29223807]
[42]
Chen, T.; Ning, M.; Ye, Y.; Wang, K.; Leng, Y.; Shen, J. Design, synthesis and structure−activity relationship studies of GPR40 agonists containing amide linker. Eur. J. Med. Chem., 2018, 152, 175-194.
[http://dx.doi.org/10.1016/j.ejmech.2018.04.023] [PMID: 29705709]
[43]
Sun, Z.; Zhou, T.; Pan, X.; Yang, Y.; Huan, Y.; Xiao, Z.; Shen, Z.; Liu, Z. Design, synthesis and biological evaluation of a series of novel GPR40 agonists containing nitrogen heterocyclic rings. Bioorg. Med. Chem. Lett., 2018, 28(18), 3050-3056.
[http://dx.doi.org/10.1016/j.bmcl.2018.07.048] [PMID: 30097366]
[44]
Li, Z.; Chen, Y.; Zhang, Y.; Jiang, H.; Liu, Y.; Chen, Y.; Zhang, L.; Qian, H. Structure-based design of free fatty acid receptor 1 agonists bearing non-biphenyl scaffold. Bioorg. Chem., 2018, 80, 296-302.
[http://dx.doi.org/10.1016/j.bioorg.2018.06.039] [PMID: 29980115]
[45]
Li, Z.; Zhou, Z.; Deng, F.; Li, Y.; Zhang, D.; Zhang, L. Design, synthesis, and biological evaluation of novel pan agonists of FFA1, PPARγ and PPARδ. Eur. J. Med. Chem., 2018, 159, 267-276.
[http://dx.doi.org/10.1016/j.ejmech.2018.09.071] [PMID: 30296685]
[46]
Yang, J.; Gu, E.; Yan, T.; Shen, D.; Feng, B.; Tang, C. Design, synthesis, and evaluation of a series of novel phenylpropanoic acid derivatives agonists for the FFA1. Chem. Biol. Drug Des., 2019, 93(5), 900-909.
[http://dx.doi.org/10.1111/cbdd.13480] [PMID: 30657643]
[47]
Kong, D.; Guo, S.; Yang, Y.; Guo, B.; Xie, X.; Hu, W. Synthesis and biological evaluation of novel potent FFA1 agonists containing 2,3-dihydrobenzo[b][1,4]dioxine. Bioorg. Med. Chem. Lett., 2019, 29(6), 848-852.
[http://dx.doi.org/10.1016/j.bmcl.2019.01.014] [PMID: 30685095]
[48]
Li, Z.; Liu, C.; Yang, J.; Zhou, J.; Ye, Z.; Feng, D.; Yue, N.; Tong, J.; Huang, W.; Qian, H. Design, synthesis and biological evaluation of novel FFA1/GPR40 agonists: New breakthrough in an old scaffold. Eur. J. Med. Chem., 2019, 179, 608-622.
[http://dx.doi.org/10.1016/j.ejmech.2019.06.087] [PMID: 31279294]
[49]
Chen, Y.; Ren, Q.; Zhou, Z.; Deng, L.; Hu, L.; Zhang, L.; Li, Z. HWL‐088, a new potent free fatty acid receptor 1 (FFAR1) agonist, improves glucolipid metabolism and acts additively with metformin in ob/ob diabetic mice. Br. J. Pharmacol., 2020, 177(10), 2286-2302.
[http://dx.doi.org/10.1111/bph.14980] [PMID: 31971610]
[50]
Li, Z.; Liu, C.; Zhou, Z.; Hu, L.; Deng, L.; Ren, Q.; Qian, H. A novel FFA1 agonist, CPU025, improves glucose-lipid metabolism and alleviates fatty liver in obese-diabetic (ob/ob) mice. Pharmacol. Res., 2020, 153, 104679.
[http://dx.doi.org/10.1016/j.phrs.2020.104679] [PMID: 32014571]
[51]
Kuranov, S.O.; Luzina, O.A.; Onopchenko, O.; Pishel, I.; Zozulya, S.; Gureev, M.; Salakhutdinov, N.F.; Krasavin, M. Exploring bulky natural and natural-like periphery in the design of p-(benzyloxy)phenylpropionic acid agonists of free fatty acid receptor 1 (GPR40). Bioorg. Chem., 2020, 99, 103830.
[http://dx.doi.org/10.1016/j.bioorg.2020.103830] [PMID: 32289588]
[52]
Ye, Z.; Liu, C.; Zou, F.; Cai, Y.; Chen, B.; Zou, Y.; Mo, J.; Han, T.; Huang, W.; Qiu, Q.; Qian, H. Discovery of novel potent GPR40 agonists containing imidazo[1,2-a]pyridine core as antidiabetic agents. Bioorg. Med. Chem., 2020, 28(13), 115574.
[http://dx.doi.org/10.1016/j.bmc.2020.115574] [PMID: 32546302]
[53]
Li, Z.; Zhou, Z.; Hu, L.; Deng, L.; Ren, Q.; Zhang, L. ZLY032, the first-in-class dual FFA1/PPARδ agonist, improves glucolipid metabolism and alleviates hepatic fibrosis. Pharmacol. Res., 2020, 159, 105035.
[http://dx.doi.org/10.1016/j.phrs.2020.105035] [PMID: 32562818]
[54]
Ulven, T. Short-chain free fatty acid receptors FFA2/GPR43 and FFA3/GPR41 as new potential therapeutic targets. Front. Endocrinol. (Lausanne), 2012, 3, 111.
[http://dx.doi.org/10.3389/fendo.2012.00111] [PMID: 23060857]
[55]
Sleeth, M.L.; Thompson, E.L.; Ford, H.E.; Zac-Varghese, S.E.K.; Frost, G. Free fatty acid receptor 2 and nutrient sensing: A proposed role for fibre, fermentable carbohydrates and short-chain fatty acids in appetite regulation. Nutr. Res. Rev., 2010, 23(1), 135-145.
[http://dx.doi.org/10.1017/S0954422410000089] [PMID: 20482937]
[56]
Tolhurst, G.; Heffron, H.; Lam, Y.S.; Parker, H.E.; Habib, A.M.; Diakogiannaki, E.; Cameron, J.; Grosse, J.; Reimann, F.; Gribble, F.M. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes, 2012, 61(2), 364-371.
[http://dx.doi.org/10.2337/db11-1019] [PMID: 22190648]
[57]
Wang, Y.; Jiao, X.; Kayser, F.; Liu, J.; Wang, Z.; Wanska, M.; Greenberg, J.; Weiszmann, J.; Ge, H.; Tian, H.; Wong, S.; Schwandner, R.; Lee, T.; Li, Y. The first synthetic agonists of FFA2: Discovery and SAR of phenylacetamides as allosteric modulators. Bioorg. Med. Chem. Lett., 2010, 20(2), 493-498.
[http://dx.doi.org/10.1016/j.bmcl.2009.11.112] [PMID: 20005104]
[58]
Schmidt, J.; Smith, N.J.; Christiansen, E.; Tikhonova, I.G.; Grundmann, M.; Hudson, B.D.; Ward, R.J.; Drewke, C.; Milligan, G.; Kostenis, E.; Ulven, T. Selective orthosteric free fatty acid receptor 2 (FFA2) agonists: Identification of the structural and chemical requirements for selective activation of FFA2 versus FFA3. J. Biol. Chem., 2011, 286(12), 10628-10640.
[http://dx.doi.org/10.1074/jbc.M110.210872] [PMID: 21220428]
[59]
Hudson, B.D.; Due-Hansen, M.E.; Christiansen, E.; Hansen, A.M.; Mackenzie, A.E.; Murdoch, H.; Pandey, S.K.; Ward, R.J.; Marquez, R.; Tikhonova, I.G.; Ulven, T.; Milligan, G. Defining the molecular basis for the first potent and selective orthosteric agonists of the FFA2 free fatty acid receptor. J. Biol. Chem., 2013, 288(24), 17296-17312.
[http://dx.doi.org/10.1074/jbc.M113.455337] [PMID: 23589301]
[60]
Forbes, S.; Stafford, S.; Coope, G.; Heffron, H.; Real, K.; Newman, R.; Davenport, R.; Barnes, M.; Grosse, J.; Cox, H. Selective FFA2 agonism appears to act via intestinal PYY to reduce transit and food intake but does not improve glucose tolerance in mouse models. Diabetes, 2015, 64(11), 3763-3771.
[http://dx.doi.org/10.2337/db15-0481] [PMID: 26239054]
[61]
Park, B.-O.; Kim, S. H.; Kong, G. Y.; Kim, D. H.; Kwon, M. S.; Lee, S. U.; Kim, M.-O.; Cho, S.; Lee, S.; Lee, H.-J.; Han, S.-B.; Kwak, Y. S.; Lee, S. B.; Kim, S. Selective novel inverse agonists for human GPR43 augment GLP-1 secretion. Eur. J. Pharmacol., 2016, 771, 1-9.
[http://dx.doi.org/10.1016/j.ejphar.2015.12.010]
[62]
Hansen, A.H.; Sergeev, E.; Bolognini, D.; Sprenger, R.R.; Ekberg, J.H.; Ejsing, C.S.; McKenzie, C.J.; Rexen Ulven, E.; Milligan, G.; Ulven, T. Discovery of a potent thiazolidine free fatty acid receptor 2 agonist with favorable pharmacokinetic properties. J. Med. Chem., 2018, 61(21), 9534-9550.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00855] [PMID: 30247908]
[63]
Hoveyda, H.R.; Fraser, G.L.; Zoute, L.; Dutheuil, G.; Schils, D.; Brantis, C.; Lapin, A.; Parcq, J.; Guitard, S.; Lenoir, F.; Bousmaqui, M.E.; Rorive, S.; Hospied, S.; Blanc, S.; Bernard, J.; Ooms, F.; McNelis, J.C.; Olefsky, J.M. N-Thiazolylamide-based free fatty-acid 2 receptor agonists: Discovery, lead optimization and demonstration of off-target effect in a diabetes model. Bioorg. Med. Chem., 2018, 26(18), 5169-5180.
[http://dx.doi.org/10.1016/j.bmc.2018.09.015] [PMID: 30253886]
[64]
Ichimura, A.; Hasegawa, S.; Kasubuchi, M.; Kimura, I. Free fatty acid receptors as therapeutic targets for the treatment of diabetes. Front. Pharmacol., 2014, 5, 236.
[http://dx.doi.org/10.3389/fphar.2014.00236] [PMID: 25414667]
[65]
Lin, H.V.; Frassetto, A.; Kowalik, E.J., Jr; Nawrocki, A.R.; Lu, M.M.; Kosinski, J.R.; Hubert, J.A.; Szeto, D.; Yao, X.; Forrest, G.; Marsh, D.J. Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms. PLoS One, 2012, 7(4), e35240.
[http://dx.doi.org/10.1371/journal.pone.0035240] [PMID: 22506074]
[66]
Kimura, I.; Ozawa, K.; Inoue, D.; Imamura, T.; Kimura, K.; Maeda, T.; Terasawa, K.; Kashihara, D.; Hirano, K.; Tani, T.; Takahashi, T.; Miyauchi, S.; Shioi, G.; Inoue, H.; Tsujimoto, G. The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat. Commun., 2013, 4(1), 1829.
[http://dx.doi.org/10.1038/ncomms2852] [PMID: 23652017]
[67]
Samuel, B.S.; Shaito, A.; Motoike, T.; Rey, F.E.; Backhed, F.; Manchester, J.K.; Hammer, R.E.; Williams, S.C.; Crowley, J.; Yanagisawa, M.; Gordon, J.I. Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc. Natl. Acad. Sci. USA, 2008, 105(43), 16767-16772.
[http://dx.doi.org/10.1073/pnas.0808567105] [PMID: 18931303]
[68]
Leonard James, N.; Chu, Zhi Liang; Bruce Marc, A.; Boatman, P. GPR41 and modulators thereof for the treatment of insulin-related disorders. WO2006052566A2, 2006.
[69]
Hudson, B.D.; Christiansen, E.; Murdoch, H.; Jenkins, L.; Hansen, A.H.; Madsen, O.; Ulven, T.; Milligan, G. Complex pharmacology of novel allosteric free fatty acid 3 receptor ligands. Mol. Pharmacol., 2014, 86(2), 200-210.
[http://dx.doi.org/10.1124/mol.114.093294] [PMID: 24870406]
[70]
Engelstoft, M.S.; Park, W.; Sakata, I.; Kristensen, L.V.; Husted, A.S.; Osborne-Lawrence, S.; Piper, P.K.; Walker, A.K.; Pedersen, M.H.; Nøhr, M.K.; Pan, J.; Sinz, C.J.; Carrington, P.E.; Akiyama, T.E.; Jones, R.M.; Tang, C.; Ahmed, K.; Offermanns, S.; Egerod, K.L.; Zigman, J.M.; Schwartz, T.W. Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells. Mol. Metab., 2013, 2(4), 376-392.
[http://dx.doi.org/10.1016/j.molmet.2013.08.006] [PMID: 24327954]
[71]
Nøhr, M.K.; Pedersen, M.H.; Gille, A.; Egerod, K.L.; Engelstoft, M.S.; Husted, A.S.; Sichlau, R.M.; Grunddal, K.V.; Seier Poulsen, S.; Han, S.; Jones, R.M.; Offermanns, S.; Schwartz, T.W. GPR41/FFAR3 and GPR43/FFAR2 as cosensors for short-chain fatty acids in enteroendocrine cells vs. FFAR3 in enteric neurons and FFAR2 in enteric leukocytes. Endocrinology, 2013, 154(10), 3552-3564.
[http://dx.doi.org/10.1210/en.2013-1142] [PMID: 23885020]
[72]
Ulven, E.R.; Quon, T.; Sergeev, E.; Barki, N.; Brvar, M.; Hudson, B.D.; Dutta, P.; Hansen, A.H.; Bielefeldt, L.Ø.; Tobin, A.B.; McKenzie, C.J.; Milligan, G.; Ulven, T. Structure–activity relationship studies of tetrahydroquinolone free fatty acid receptor 3 modulators. J. Med. Chem., 2020, 63(7), 3577-3595.
[http://dx.doi.org/10.1021/acs.jmedchem.9b02036] [PMID: 32141297]
[73]
Oh, D.Y.; Talukdar, S.; Bae, E.J.; Imamura, T.; Morinaga, H.; Fan, W.; Li, 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(5), 687-698.
[http://dx.doi.org/10.1016/j.cell.2010.07.041] [PMID: 20813258]
[74]
Li, A.; Li, Y.; Du, L. Biological characteristics and agonists of GPR120 (FFAR4) receptor: The present status of research. Future Med. Chem., 2015, 7(11), 1457-1468.
[http://dx.doi.org/10.4155/fmc.15.75] [PMID: 26230883]
[75]
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(1), 90-94.
[http://dx.doi.org/10.1038/nm1168] [PMID: 15619630]
[76]
Oh, D.Y.; Olefsky, J.M. Omega 3 fatty acids and GPR120. Cell Metab., 2012, 15(5), 564-565.
[http://dx.doi.org/10.1016/j.cmet.2012.04.009] [PMID: 22560206]
[77]
Sun, Q.; Hirasawa, A.; Hara, T.; Kimura, I.; Adachi, T.; Awaji, T.; Ishiguro, M.; Suzuki, T.; Miyata, N.; Tsujimoto, G. Structure-activity relationships of GPR120 agonists based on a docking simulation. Mol. Pharmacol., 2010, 78(5), 804-810.
[http://dx.doi.org/10.1124/mol.110.066324] [PMID: 20685848]
[78]
Shimpukade, B.; Hudson, B.D.; Hovgaard, C.K.; Milligan, G.; Ulven, T. Discovery of a potent and selective GPR120 agonist. J. Med. Chem., 2012, 55(9), 4511-4515.
[http://dx.doi.org/10.1021/jm300215x] [PMID: 22519963]
[79]
Sparks, S.M.; Chen, G.; Collins, J.L.; Danger, D.; Dock, S.T.; Jayawickreme, C.; Jenkinson, S.; Laudeman, C.; Leesnitzer, M.A.; Liang, X.; Maloney, P.; McCoy, D.C.; Moncol, D.; Rash, V.; Rimele, T.; Vulimiri, P.; Way, J.M.; Ross, S. Identification of diarylsulfonamides as agonists of the free fatty acid receptor 4 (FFA4/GPR120). Bioorg. Med. Chem. Lett., 2014, 24(14), 3100-3103.
[http://dx.doi.org/10.1016/j.bmcl.2014.05.012] [PMID: 24881566]
[80]
Azevedo, C.M.G.; Watterson, K.R.; Wargent, E.T.; Hansen, S.V.F.; Hudson, B.D.; Kępczyńska, M.A.; Dunlop, J.; Shimpukade, B.; Christiansen, E.; Milligan, G.; Stocker, C.J.; Ulven, T. Non-acidic free fatty acid receptor 4 agonists with antidiabetic activity. J. Med. Chem., 2016, 59(19), 8868-8878.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00685] [PMID: 27570890]
[81]
Lombardo, M.; Bender, K.; London, C.; Plotkin, M.A.; Kirkland, M.; Mane, J.; Pachanski, M.; Geissler, W.; Cummings, J.; Habulihaz, B.; Akiyama, T.E.; Di Salvo, J.; Madeira, M.; Pols, J.; Powles, M.A.; Finley, M.F.; Johnson, E.; Roussel, T.; Uebele, V.N. Discovery of benzofuran propanoic acid GPR120 agonists: From uHTS hit to mechanism-based pharmacodynamic effects. Bioorg. Med. Chem. Lett., 2016, 26(23), 5724-5728.
[http://dx.doi.org/10.1016/j.bmcl.2016.10.054]
[82]
Cox, J.M.; Chu, H.D.; Chelliah, M.V.; Debenham, J.S.; Eagen, K.; Lan, P.; Lombardo, M.; London, C.; Plotkin, M.A.; Shah, U.; Sun, Z.; Vaccaro, H.M.; Venkatraman, S.; Suzuki, T.; Wang, N.; Ashley, E.R.; Crespo, A.; Madeira, M.; Leung, D.H.; Alleyne, C.; Ogawa, A.M.; Souza, S.; Thomas-Fowlkes, B.; Di Salvo, J.; Weinglass, A.; Kirkland, M.; Pachanski, M.; Powles, M.A.; Tozzo, E.; Akiyama, T.E.; Ujjainwalla, F.; Tata, J.R.; Sinz, C.J. Design, synthesis, and evaluation of novel and selective G-protein coupled receptor 120 (GPR120) spirocyclic agonists. ACS Med. Chem. Lett., 2017, 8(1), 49-54.
[http://dx.doi.org/10.1021/acsmedchemlett.6b00360] [PMID: 28105274]
[83]
Adams, G.L.; Velazquez, F.; Jayne, C.; Shah, U.; Miao, S.; Ashley, E.R.; Madeira, M.; Akiyama, T.E.; Di Salvo, J.; Suzuki, T.; Wang, N.; Truong, Q.; Gilbert, E.; Zhou, D.; Verras, A.; Kirkland, M.; Pachanski, M.; Powles, M.; Yin, W.; Ujjainwalla, F.; Venkatraman, S.; Edmondson, S.D. Discovery of chromane propionic acid analogues as selective agonists of GPR120 with in vivo activity in rodents. ACS Med. Chem. Lett., 2017, 8(1), 96-101.
[http://dx.doi.org/10.1021/acsmedchemlett.6b00394] [PMID: 28105282]
[84]
Sparks, S.M.; Aquino, C.; Banker, P.; Collins, J.L.; Cowan, D.; Diaz, C.; Dock, S.T.; Hertzog, D.L.; Liang, X.; Swiger, E.D.; Yuen, J.; Chen, G.; Jayawickreme, C.; Moncol, D.; Nystrom, C.; Rash, V.; Rimele, T.; Roller, S.; Ross, S. Exploration of phenylpropanoic acids as agonists of the free fatty acid receptor 4 (FFA4): Identification of an orally efficacious FFA4 agonist. Bioorg. Med. Chem. Lett., 2017, 27(5), 1278-1283.
[http://dx.doi.org/10.1016/j.bmcl.2017.01.034] [PMID: 28148462]
[85]
McCoull, W.; Bailey, A.; Barton, P.; Birch, A.M.; Brown, A.J.H.; Butler, H.S.; Boyd, S.; Butlin, R.J.; Chappell, B.; Clarkson, P.; Collins, S.; Davies, R.M.D.; Ertan, A.; Hammond, C.D.; Holmes, J.L.; Lenaghan, C.; Midha, A.; Morentin-Gutierrez, P.; Moore, J.E.; Raubo, P.; Robb, G. Indazole-6-phenylcyclopropylcarboxylic acids as selective GPR120 agonists with in vivo efficacy. J. Med. Chem., 2017, 60(7), 3187-3197.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00210] [PMID: 28374589]
[86]
Zhang, X.; Cai, C.; Winters, M.; Wells, M.; Wall, M.; Lanter, J.; Sui, Z.; Ma, J.; Novack, A.; Nashashibi, I.; Wang, Y.; Yan, W.; Suckow, A.; Hua, H.; Bell, A.; Haug, P.; Clapper, W.; Jenkinson, C.; Gunnet, J.; Leonard, J.; Murray, W.V. Design, synthesis and SAR of a novel series of heterocyclic phenylpropanoic acids as GPR120 agonists. Bioorg. Med. Chem. Lett., 2017, 27(15), 3272-3278.
[http://dx.doi.org/10.1016/j.bmcl.2017.06.028] [PMID: 28642104]
[87]
Li, Z.; Xu, X.; Li, G.; Fu, X.; Liu, Y.; Feng, Y.; Wang, M.; Ouyang, Y.; Han, J. Improving metabolic stability with deuterium: The discovery of GPU-028, a potent free fatty acid receptor 4 agonists. Bioorg. Med. Chem., 2017, 25(24), 6647-6652.
[http://dx.doi.org/10.1016/j.bmc.2017.10.040] [PMID: 29100735]
[88]
Winters, M.P.; Sui, Z.; Wall, M.; Wang, Y.; Gunnet, J.; Leonard, J.; Hua, H.; Yan, W.; Suckow, A.; Bell, A.; Clapper, W.; Jenkinson, C.; Haug, P.; Koudriakova, T.; Huebert, N.; Murray, W.V. Discovery of N -arylpyrroles as agonists of GPR120 for the treatment of type II diabetes. Bioorg. Med. Chem. Lett., 2018, 28(5), 841-846.
[http://dx.doi.org/10.1016/j.bmcl.2018.02.013] [PMID: 29456108]