Free fatty acid receptor agonists for the treatment of type 2 diabetes: drugs in preclinical to phase II clinical development

References

• DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773–795.
   PubMed Web of Science ®Google Scholar
• Danaei G, Finucane MM, Lu Y, et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet. 2011;378:31–40.
   PubMed Web of Science ®Google Scholar
• Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001;414:799–806.
   PubMed Web of Science ®Google Scholar
• Bailey CJ. Safety of antidiabetes medications: an update. Clin. Pharmacol. Ther. 2015;98:185–195.
   PubMed Web of Science ®Google Scholar
• Stein SA, Lamos EM, Davis SN. A review of the efficacy and safety of oral antidiabetic drugs. Expert Opin Drug Saf. 2013;12:153–175.
   PubMed Web of Science ®Google Scholar
• Phung OJ, Scholle JM, Talwar M, et al. Effect of noninsulin antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes. JAMA. 2010;303:1410–1418.
   PubMed Web of Science ®Google Scholar
• Avery MA, Mizuno CS, Chittiboyina AG, et al. Type 2 diabetes and oral antihyperglycemic drugs. Curr Med Chem. 2008;15:61–74.
   PubMed Web of Science ®Google Scholar
• Lebovitz HE. Type 2 diabetes mellitus—current therapies and the emergence of surgical options. Nat Rev Endocrinol. 2011;7:408–419.
   PubMed Web of Science ®Google Scholar
• Scheen AJ. Safety of dipeptidyl peptidase-4 inhibitors for treating type 2 diabetes. Expert Opin Drug Saf. 2015;14:505–524.
   PubMed Web of Science ®Google Scholar
• Tahrani AA, Bailey CJ, Del Prato S, et al. Management of type 2 diabetes: new and future developments in treatment. Lancet. 2011;378:182–197.
   PubMed Web of Science ®Google Scholar
• Xu X, Wang G, Zhou T, et al. Novel approaches to drug discovery for the treatment of type 2 diabetes. Expert Opin Drug Dis. 2014;9:1047–1058.
   PubMed Web of Science ®Google Scholar
• Kahn SE, Buse JB. Medications for type 2 diabetes: how will we be treating patients in 50 years? Diabetologia. 2015;58:1735–1739.
   PubMed Web of Science ®Google Scholar
• Bhatt HB. Thoughts on the progression of type 2 diabetes drug discovery. Expert Opin Drug Dis. 2015;10:107–110.
   PubMed Web of Science ®Google Scholar
• McGarry JD, Dobbins RL. Fatty acids, lipotoxicity and insulin secretion. Diabetologia. 1999;42:128–138.
   PubMed Web of Science ®Google Scholar
• Dobbins RL, Chester MM, Daniels MB, et al. Circulating fatty acids are essential for efficient glucose-stimulated insulin secretion after prolonged fasting in humans. Diabetes. 1998;47:1613–1618.
   PubMed Web of Science ®Google Scholar
• Nolan CJ, Madiraju MSR, Delghingaro-Augusto V, et al. Fatty acid signaling in the beta-cell and insulin secretion. Diabetes. 2006;55:S16–S23.
   PubMed Web of Science ®Google Scholar
• Itoh Y, Kawamata Y, Harada M, et al. Free fatty acids regulate insulin secretion from pancreatic β cells through GPR40. Nature. 2003;422:173–176.
   PubMed Web of Science ®Google Scholar
• Briscoe CP, Tadayyon M, Andrews JL, et al. The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J Biol Chem. 2003;278:11303–11311.
   PubMed Web of Science ®Google Scholar
• Stoddart LA, Smith NJ, Milligan G. International union of pharmacology. LXXI. Free fatty acid receptors FFA1, −2, and-3: pharmacology and pathophysiological functions. Pharmacol Rev. 2008;60:405–417.
   PubMed Web of Science ®Google Scholar
• Wellendorph P, Johansen LD, Bräuner-Osborne H. Molecular pharmacology of promiscuous seven transmembrane receptors sensing organic nutrients. Mol Pharmacol. 2009;76:453–465.
   PubMed Web of Science ®Google Scholar
• Brown AJ, Goldsworthy SM, Barnes AA, et al. The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem. 2003;278:11312–11319.
   PubMed Web of Science ®Google Scholar
• Le Poul E, Loison C, Struyf S, et al. Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J Biol Chem. 2003;278:25481–25489.
   PubMed Web of Science ®Google Scholar
• Tang C, Ahmed K, Gille A, et al. Loss of FFA2 and FFA3 increases insulin secretion and improves glucose tolerance in type 2 diabetes. Nat Med. 2015;21:85–89.
   Web of Science ®Google Scholar
• Hirasawa A, Tsumaya K, Awaji T, et al. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med. 2005;11:90–94.
   PubMed Web of Science ®Google Scholar
• Oh DY, Talukdar S, Bae EJ, et al. GPR120 is an Omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell. 2010;142:687–698.
   PubMed Web of Science ®Google Scholar
• Poitout V, Lin DCH. Modulating GPR40: therapeutic promise and potential in diabetes. Drug Discov Today. 2013;18:1301–1308.
   PubMed Web of Science ®Google Scholar
• Yonezawa T, Kurata R, Yoshida K, et al. Free fatty acids-sensing G protein-coupled receptors in drug targeting and therapeutics. Curr Med Chem. 2013;20:3855–3871.
   PubMed Web of Science ®Google Scholar
• Zietek T, Daniel H. Intestinal nutrient sensing and blood glucose control. Curr Opin Clin Nutr. 2015;18:381–388.
   PubMed Web of Science ®Google Scholar
• Nakamura MT, Yudell BE, Loor JJ. Regulation of energy metabolism by long-chain fatty acids. Prog Lipid Res. 2014;53:124–144.
   PubMed Web of Science ®Google Scholar
• Bindels LB, Dewulf EM, Delzenne NM. GPR43/FFA2: physiopathological relevance and therapeutic prospects. Trends Pharmacol Sci. 2013;34:226–232.
   PubMed Web of Science ®Google Scholar
• Li A, Li Y, Du L. Biological characteristics and agonists of GPR120 (FFAR4) receptor: the present status of research. Future Med Chem. 2015;7:1457–1468.
   PubMed Web of Science ®Google Scholar
• Moniri NH. Free-fatty acid receptor-4 (GPR120): cellular and molecular function and its role in metabolic disorders. Biochem Pharmacol;2016. doi:10.1016/j.bcp.2016.01.021. [Epub ahead of print]
   PubMed Web of Science ®Google Scholar
• Yamashima T. Dual effects of the non-esterified fatty acid receptor ‘GPR40ʹ for human health. Prog Lipid Res. 2015;58:40–50.
   PubMed Web of Science ®Google Scholar
• Shapiro H, Shachar S, Sekler I, et al. Role of GPR40 in fatty acid action on the beta cell line INS-1E. Biochem Biophys Res Commun. 2005;335:97–104.
   PubMed Web of Science ®Google Scholar
• Fujiwara K, Maekawa F, Yada T. Oleic acid interacts with GPR40 to induce Ca2+ signaling in rat islet beta-cells: mediation by PLC and L-type Ca2+ channel and link to insulin release. Am J Physiol Endocrinol Metab. 2005;289:E670–E677.
   PubMed Web of Science ®Google Scholar
• Schnell S, Schaefer M, Schoefl C. Free fatty acids increase cytosolic free calcium and stimulate insulin secretion from beta-cells through activation of GPR40. Mol Cell Endocrinol. 2007;263:173–180.
   PubMed Web of Science ®Google Scholar
• Tan CP, Feng Y, Zhou Y-P, et al. Selective small-molecule agonists of G protein-coupled receptor 40 promote glucose-dependent insulin secretion and reduce blood glucose in mice. Diabetes. 2008;57:2211–2219.
   PubMed Web of Science ®Google Scholar
• Tsujihata Y, Ito R, Suzuki M, et al. TAK-875, an orally available g protein-coupled receptor 40/free fatty acid receptor 1 agonist, enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia in type 2 diabetic rats. J Pharmacol Exp Ther. 2011;339:228–237.
   PubMed Web of Science ®Google Scholar
• Edfalk S, Steneberg P, Edlund H. Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion. Diabetes. 2008;57:2280–2287.
   PubMed Web of Science ®Google Scholar
• Luo J, Swaminath G, Brown SP, et al. A potent class of GPR40 full agonists engages the enteroinsular axis to promote glucose control in rodents. PloS One. 2012;7:e46300.
   PubMed Web of Science ®Google Scholar
• Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87:1409–1439.
   PubMed Web of Science ®Google Scholar
• Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132:2131–2157.
   PubMed Web of Science ®Google Scholar
• Tanaka T, Yano T, Adachi T, et al. 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. N-S Arch Pharmacol. 2008;377:515–522.
   PubMed Web of Science ®Google Scholar
• Liu Y, Chen L-Y, Sokolowska M, et al. The fish oil ingredient, docosahexaenoic acid, activates cytosolic phospholipase A(2) via GPR120 receptor to produce prostaglandin E-2 and plays an anti-inflammatory role in macrophages. Immunology. 2014;143:81–95.
   PubMed Web of Science ®Google Scholar
• Gotoh C, Hong Y-H, Iga T, et al. The regulation of adipogenesis through GPR120. Biochem Biophys Res Commun. 2007;354:591–597.
   PubMed Web of Science ®Google Scholar
• Oh DY, Walenta E, Akiyama TE, et al. A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice. Nat Med. 2014;20:942–947.
   PubMed Web of Science ®Google Scholar
• Garrido DM, Corbett DF, Dwornik KA, et al. Synthesis and activity of small molecule GPR40 agonists. Bioorg Med Chem Lett. 2006;16:1840–1845.
   PubMed Web of Science ®Google Scholar
• McKeown SC, Corbett DF, Goetz AS, et al. Solid phase synthesis and SAR of small molecule agonists for the GPR40 receptor. Bioorg Med Chem Lett. 2007;17:1584–1589.
   PubMed Web of Science ®Google Scholar
• Brown SP, Dransfield PJ, Vimolratana M, et al. Discovery of AM-1638: a potent and orally bioavailable GPR40/FFA1 full agonist. ACS Med Chem Lett. 2012;3:726–730.
   PubMed Web of Science ®Google Scholar
• Wang Y, Liu J, Dransfield PJ, et al. Discovery and optimization of potent GPR40 full agonists containing tricyclic spirocycles. ACS Med Chem Lett. 2013;4:551–555.
   PubMed Web of Science ®Google Scholar
• Gowda N, Dandu A, Singh J, et al. Treatment with CNX-011-67, a novel GPR40 agonist, delays onset and progression of diabetes and improves beta cell preservation and function in male ZDF rats. BMC Pharmacol Toxicol. 2013;14:1–13.
   PubMed Web of Science ®Google Scholar
• Gudla CS, Prasad HS, Karuppaiah R, et al. Process for the Preparation of an Aryl Oxime and Salts Thereof. WO2013057743. 2013.
   Google Scholar
• Christiansen E, Hansen SVF, Urban C, et al. Discovery of TUG-770: a highly potent free fatty acid receptor 1 (FFA1/GPR40) agonist for treatment of type 2 diabetes. ACS Med Chem Lett. 2013;4:441–445.
   PubMed Web of Science ®Google Scholar
• Negoro K, Iwasaki F, Ohnuki K, et al., Oxadiazolidinedione Compound. WO2007123225. 2007.
   Google Scholar
• Astellas. Novel Salt of Oxadiazolidinedione, and Crystal Thereof. JP2013184934. 2013.
   Google Scholar
• Negoro K, Ohnuki K, Yonetoku Y, et al. Carboxylic Acid Compound. WO2010123016. 2010.
   Google Scholar
• Tanaka H, Yoshida S, Minoura H, et al. Novel GPR40 agonist AS2575959 exhibits glucose metabolism improvement and synergistic effect with sitagliptin on insulin and incretin secretion. Life Sci. 2014;94:115–121.
   PubMed Web of Science ®Google Scholar
• Defossa E, Dietrich V, Klabunde T, et al. 3-[4-(Phenylaminooxalylamino)phenyl] hex-4-ynoic Acids, Process for Preparation Thereof and Use Thereof as a Medicament. WO2013102626. 2013.
   Google Scholar
• Keil S, Defossa E, Dietrich V, et al., Aryloxy-Alkylene Substituted Hydroxyphenyl Heyxnoic Acids, Methods for the Production Thereof and Use of the Same as Medicament. WO2012010413. 2012.
   Google Scholar
• Takano R, Yoshida M, Inoue M, et al. Discovery of DS-1558: a potent and orally bioavailable GPR40 agonist. ACS Med Chem Lett. 2015;6:266–270.
   PubMed Web of Science ®Google Scholar
• Takano R, Yoshida M, Inoue M, et al. Optimization of 3-aryl-3-ethoxypropanoic acids and discovery of the potent GPR40 agonist DS-1558. Bioorgan Med Chem. 2015;23:5546–5565.
   PubMed Web of Science ®Google Scholar
• Ellsworth BA, Ewing WR, Jurica EA, et al., Dihydropyrazole GPR40 Modulators. WO2014078610. 2014.
   Google Scholar
• Ellsworth BA, Shi J, Jurica EA, et al. Discovery of BMS-986118, a dual MOA GPR40 agonist that produces glucose-dependent insulin and GLP-1 secretion. 248th American Chemical Society National Meeting & Exposition; 2014 Aug 10–14; San Francisco, CA. Abstract MEDI 31.
   Google Scholar
• Kim SC, Jung SY, Chung YM. Synthesis and biological evaluation of sulfonyl moieties as GPR40 agonist. 10th AFMC International Medicinal Chemistry Symposium (AIMECS); 2015 Oct 18–21; Jeju. Abstract PP1-99.
   Google Scholar
• Himmelsbach F, Bakker R, Eckhardt M, et al., Indanyloxydihydrobenzofuranylacetic Acids.WO2012072691. 2012.
   Google Scholar
• Lingard I, Hamprecht D, New Indanyloxyphenylcyclopropanecarboxylic Acids. WO2015078802. 2015.
   Google Scholar
• Walsh SP, Severino A, Zhou C, et al. 3-Substituted 3-(4-aryloxyaryl)-propanoic acids as GPR40 agonists. Bioorg Med Chem Lett. 2011;21:3390–3394.
   PubMed Web of Science ®Google Scholar
• Hagmann WK, Nargund RP, Blizzard TA, et al., Antidiabetic tricyclic compounds. WO2014022528. 2014.
   Google Scholar
• Player MR, Huang H, Meegalla S, Pyrazine GPR40 Agonists for the Treatment of Type II Diabetes. WO2016007714. 2016.
   Google Scholar
• Lu H, Fei H, Yang F, et al. Discovery of novel orally bioavailable GPR40 agonists. Bioorg Med Chem Lett. 2013;23:2920–2924.
   PubMed Web of Science ®Google Scholar
• Desai RC, Srivastava B, Novel Heterocyclic Compounds. WO2015097713. 2015.
   Google Scholar
• Guo D-Y, Li D-W, Ning -M-M, et al. Yhhu4488, a novel GPR40 agonist, promotes GLP-1 secretion and exerts anti-diabetic effect in rodent models. Biochem Bioph Res Co. 2015;466:740–747.
   PubMed Web of Science ®Google Scholar
• Wang X, Zhao T, Yang B, et al. Synthesis and biological evaluation of phenoxyacetic acid derivatives as novel free fatty acid receptor 1 agonists. Bioorgan Med Chem. 2015;23:132–140.
   PubMed Web of Science ®Google Scholar
• Li Z, Wang X, Xu X, et al. Design, synthesis and biological activity of phenoxyacetic acid derivatives as novel free fatty acid receptor 1 agonists. Bioorgan Med Chem. 2015;23:7158–7164.
   PubMed Web of Science ®Google Scholar
• Li Z, Qiu Q, Xu X, et al. 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.
   PubMed Web of Science ®Google Scholar
• Li Z, Pan M, Su X, et al. Discovery of novel pyrrole-based scaffold as potent and orally bioavailable free fatty acid receptor 1 agonists for the treatment of type 2 diabetes. Bioorgan Med Chem. 2016;24:1981–1987.
   PubMed Web of Science ®Google Scholar
• Sasaki S, Kitamura S, Negoro N, et al. Design, synthesis, and biological activity of potent and orally available G protein-coupled receptor 40 agonists. J Med Chem. 2011;54:1365–1378.
   PubMed Web of Science ®Google Scholar
• Negoro N, Sasaki S, Mikami S, et al. Discovery of TAK-875: a potent, selective, and orally bioavailable GPR40 agonist. ACS Med Chem Lett. 2010;1:290–294.
   PubMed Web of Science ®Google Scholar
• Mikami S, Kitamura S, Negoro N, et al. Discovery of phenylpropanoic acid derivatives containing polar functionalities as potent and orally bioavailable G protein-coupled receptor 40 agonists for the treatment of type 2 diabetes. J Med Chem. 2012;55:3756–3776.
   PubMed Web of Science ®Google Scholar
• Negoro N, Sasaki S, Ito M, et al. Identification of fused-ring alkanoic acids with improved pharmacokinetic profiles that act as G protein-coupled receptor 40/free fatty acid receptor 1 agonists. J Med Chem. 2012;55:1538–1552.
   PubMed Web of Science ®Google Scholar
• Negoro N, Sasaki S, Mikami S, et al. Optimization of (2, 3-dihydro-1-benzofuran-3-yl) acetic acids: discovery of a non-free fatty acid-like, highly bioavailable G protein-coupled receptor 40/free fatty acid receptor 1 agonist as a glucose-dependent insulinotropic agent. J Med Chem. 2012;55:3960–3974.
   PubMed Web of Science ®Google Scholar
• Srivastava A, Yano J, Hirozane Y, et al. High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875. Nature. 2014;513:124–127.
   PubMed Web of Science ®Google Scholar
• Haber EP, Ximenes HMA, Procopio J, et al. Pleiotropic effects of fatty acids on pancreatic beta-cells. J Cell Physiol. 2003;194:1–12.
   PubMed Web of Science ®Google Scholar
• Ito R, Tsujihata Y, Matsuda-Nagasumi K, et al. TAK-875, a GPR40/FFAR1 agonist, in combination with metformin prevents progression of diabetes and beta-cell dysfunction in Zucker diabetic fatty rats. Brit J Pharmacol. 2013;170:568–580.
   PubMed Web of Science ®Google Scholar
• Yabuki C, Komatsu H, Tsujihata Y, et al. A novel antidiabetic drug, fasiglifam/TAK-875, acts as an ago-allosteric modulator of FFAR1. PloS One. 2013;8:e76280.
   PubMed Web of Science ®Google Scholar
• Naik H, Vakilynejad M, Wu J, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamic properties of the GPR40 agonist TAK-875: results from a double-blind, placebo-controlled single oral Dose rising study in healthy volunteers. J Clin Pharmacol. 2012;52:1007–1016.
   PubMed Web of Science ®Google Scholar
• Leifke E, Naik H, Wu J, et al. A multiple-ascending-dose study to evaluate safety, pharmacokinetics, and pharmacodynamics of a novel GPR40 agonist, TAK-875, in subjects with type 2 diabetes. Clin Pharmacol Ther. 2012;92:29–39.
   PubMed Web of Science ®Google Scholar
• Burant CF, Viswanathan P, Marcinak J, et al. TAK-875 versus placebo or glimepiride in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2012;379:1403–1411.
   PubMed Web of Science ®Google Scholar
• Kaku K, Araki T, Yoshinaka R. Randomized, double-blind, dose-ranging study of TAK-875, a novel GPR40 agonist, in Japanese patients with inadequately controlled type 2 diabetes. Diabetes Care. 2013;36:245–250.
   PubMed Web of Science ®Google Scholar
• Kaku K, Enya K, Nakaya R, et al. Efficacy and safety of fasiglifam (TAK-875), a G protein-coupled receptor 40 agonist, in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise: a randomized, double-blind, placebo-controlled, phase III trial. Diabetes Obes Metab. 2015;17:675–681.
   PubMed Web of Science ®Google Scholar
• Hedrington MS, Davis SN. Discontinued in 2013: diabetic drugs. Expert Opin Inv Drug. 2014;23:1703–1711.
   PubMed Web of Science ®Google Scholar
• Lead GPR40 agonist bites the dust. Nat Rev Drug Discov. 2014;13:91.
   Web of Science ®Google Scholar
• Li X, Zhong K, Guo Z, et al. Fasiglifam (TAK-875) inhibits hepatobiliary transporters: a possible factor contributing to fasiglifam-induced liver injury. Drug Metab Dispos: the Biological Fate of Chemicals. 2015;43:1751–1759.
   PubMed Web of Science ®Google Scholar
• Houze JB, Zhu L, Sun Y, et al. AMG 837: A potent, orally bioavailable GPR40 agonist. Bioorg Med Chem Lett. 2012;22:1267–1270.
   PubMed Web of Science ®Google Scholar
• Lin DCH, Zhang J, Zhuang R, et al. AMG 837: a novel GPR40/FFA1 agonist that enhances insulin secretion and lowers glucose levels in rodents. PloS One. 2011;6:e27270.
   PubMed Web of Science ®Google Scholar
• Steneberg P, Rubins N, Bartoov-Shifman R, et al. The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse. Cell Metab. 2005;1:245–258.
   PubMed Web of Science ®Google Scholar
• Liu J, Wang Y, Ma Z, et al. Optimization of GPR40 agonists for type 2 diabetes. ACS Med Chem Lett. 2014;5:517–521.
   PubMed Web of Science ®Google Scholar
• Ma Z, Lin DCH, Sharma R, et al. Discovery of the imidazole-derived GPR40 agonist AM-3189. Bioorg Med Chem Lett. 2016;26:15–20.
   PubMed Web of Science ®Google Scholar
• Defossa E, Wagner M. Recent developments in the discovery of FFA1 receptor agonists as novel oral treatment for type 2 diabetes mellitus. Bioorg Med Chem Lett. 2014;24:2991–3000.
   PubMed Web of Science ®Google Scholar
• Hamdouchi C, Lineswala JP, Maiti P. Spiropiperidine compounds and pharmaceutical use thereof for treating diabetes. WO2011046851. 2011.
   Google Scholar
• NCT01358981. A study of LY2881835 in healthy people and people with diabetes [Internet]. 2011 [cited 2016 Apr 20]. Available from: www.ClincialTrials.gov
   Google Scholar
• NCT01746017. A study of LY2922470 in healthy participants and participants with diabetes [Internet]. 2013 [cited 2016 Apr 20]. Available from: www.ClincialTrials.gov
   Google Scholar
• NCT01867216. A study of multiple doses of LY2922470 in participants with diabetes [Internet]. 2014 [cited 2016 Apr 20]. Available from: www.ClincialTrials.gov
   Google Scholar
• Hamdouchi C. GPR40 agonists for the treatment of type 2 diabetes: from the laboratory to the patient. 251st ACS National Meeting & Exposition. 2016 Mar 13–17; San Diego, CA. Abstract MEDI 260.
   Google Scholar
• Hamdouchi C, Lineswala JP, Maiti P, Novel Spiropiperidine Compounds. WO2011066183. 2011.
   Google Scholar
• Hamdouchi C, A Novel 1,2,3,4-Tetrahydroquinoline Derivative Useful for the Treatment of Diabetes. WO2013025424. 2013.
   Google Scholar
• NCT01699737. Safety and efficacy study of JTT-851 in patients with type 2 diabetes mellitus [Internet]. 2013 [cited 2016 Apr 20]. Available from: www.ClincialTrials.gov
   Google Scholar
• JTT851. Japan Tobacco Inc. Clinical development [Internet]. 2012 [cited 2016 Apr 20]. Available from: https://www.jt.com/investors/results/S_information/pharmaceuticals/pdf/P.L.20121030_E.pdf
   Google Scholar
• Shimada T, Ueno H, Tsutsumi K, et al., Spiro-ring compound and use thereof for medical puproses. WO2009054479. 2009.
   Google Scholar
• NCT01874366. Determination of safety, tolerability, pharmacokinetics, food effect & pharmacodynamics of single & multiple doses of P11187 [Internet]. 2014 [cited 2016 Apr 20]. Available from: www.ClinicalTrials.gov
   Google Scholar
• Kumar S, Sharma R, Mahajan VA, et al., Phenyl Alkanoic Acid Derivatives as GPR Agonists. WO2013128378. 2013.
   Google Scholar
• Meanwell NA. Synopsis of some recent tactical application of bioisosteres in drug design. J Med Chem. 2011;54:2529–2591.
   PubMed Web of Science ®Google Scholar
• CTR20150194. Multiple dosing of fusiglifam in phase I clinical trials for the treatment of type 2 diabetes [Internet]. 2015 [cited 2016 Apr 20]. Available from: http://www.chinadrugtrials.org.cn/eap/clinicaltrials.searchlistdetail
   Google Scholar
• CTR20150193. Single /multiple dosing of fusiglifam in phase I clinical trials for the healthy participants [Internet]. 2015 [cited 2016 Apr 20]. Available from: http://www.chinadrugtrials.org.cn/eap/clinicaltrials.searchlistdetail
   Google Scholar
• Yang F, Dong Q, Han J, et al., Polycyclic Derivatives, Preparation Method and Medical Uses Thereof. WO2013104257. 2013.
   Google Scholar
• Lin DCH, Guo Q, Luo J, et al. Identification and pharmacological characterization of multiple allosteric binding sites on the free fatty acid 1 receptor. Mol Pharmacol. 2012;82:843–859.
   PubMed Web of Science ®Google Scholar
• Du X, Dransfield PJ, Lin DCH, et al. Improving the pharmacokinetics of GPR40/FFA1 full agonists. ACS Med Chem Lett. 2014;5:384–389.
   PubMed Web of Science ®Google Scholar
• Sunil V, Verma MK, Oommen AM, et al. CNX-011-67, a novel GPR40 agonist, enhances glucose responsiveness, insulin secretion and islet insulin content in n-STZ rats and in islets from type 2 diabetic patients. BMC Pharmacol Toxicol. 2014;15:1–15.
   PubMed Web of Science ®Google Scholar
• Verma MK, Biswas S, Chandravanshi B, et al. A novel GPR40 agonist, CNX-011-67, suppresses glucagon secretion in pancreatic islets under chronic glucolipotoxic conditions in vitro. BMC Res Notes. 2014;7:595–595.
   PubMedGoogle Scholar
• Verma MK, Sadasivuni MK, Yateesh AN, et al. Activation of GPR40 attenuates chronic inflammation induced impact on pancreatic beta-cells health and function. BMC Cell Biol. 2014;15:1–12.
   PubMed Web of Science ®Google Scholar
• Ranganath Rao JM, Arumugam N, Ansari MM, et al., Agonists of GPR40. WO2012011125. 2012.
   Google Scholar
• Christiansen E, Urban C, Merten N, et al. 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;51:7061–7064.
   PubMed Web of Science ®Google Scholar
• Christiansen E, Due-Hansen ME, Urban C, et al. Discovery of a potent and selective free fatty acid receptor 1 agonist with low lipophilicity and high oral bioavailability. J Med Chem. 2013;56:982–992.
   PubMed Web of Science ®Google Scholar
• Tanaka H, Yoshida S, Oshima H, et al. Chronic treatment with novel GPR40 agonists improve whole-body glucose metabolism based on the glucose-dependent insulin secretion. J Pharmacol Exp Ther. 2013;346:443–452.
   PubMed Web of Science ®Google Scholar
• Negoro K, Ohnuki K, Yonetoku Y, et al., Tetrazole Compound. WO2010123017. 2010.
   Google Scholar
• Herling A, Defossa E, Haschke G, et al. Modulation of insulin secretion by GPR40 agonism. N-S Arch Pharmacol. 2011;383:6–6.
   Web of Science ®Google Scholar
• Riz M, Pedersen MG, Toffolo GM, et al. Minimal modeling of insulin secretion in the perfused rat pancreas: a drug effect case study. AM J Physiol-Endoc M. 2014;306:627–634.
   Google Scholar
• Li Z, Wang X, Xu X, et al. Design, synthesis and structure-activity relationship studies of novel phenoxyacetamide-based free fatty acid receptor 1 agonists for the treatment of type 2 diabetes. Bioorgan Med Chem. 2015;23:6666–6672.
   PubMed Web of Science ®Google Scholar
• Takano R, Yoshida M, Inoue M, et al. Discovery of 3-aryl-3-ethoxypropanoic acids as orally active GPR40 agonists. Bioorg Med Chem Lett. 2014;24:2949–2953.
   PubMed Web of Science ®Google Scholar
• Nakashima R, Yano T, Ogawa J, et al. Potentiation of insulin secretion and improvement of glucose intolerance by combining a novel G protein-coupled receptor 40 agonist DS-1558 with glucagon-like peptide-1 receptor agonists. Eur J Pharmacol. 2014;737:194–201.
   PubMed Web of Science ®Google Scholar
• Yoo JH, Kim SC, Jung SY, et al., Novel amino-phenyl-sulfonyl-acetate derivative and use thereof. WO2016032120. 2016.
   Google Scholar
• Zhou C, Tang C, Chang E, et al. Discovery of 5-aryloxy-2,4-thiazolidinediones as potent GPR40 agonists. Bioorg Med Chem Lett. 2010;20:1298–1301.
   PubMed Web of Science ®Google Scholar
• Lv H, Dong Q, Fei H, et al., Benzene and two oxygen six ring derivative, its preparation method and its application in medicine. CN103030646. 2013.
   Google Scholar
• Hu Y, Leng Y, Li D, et al., Phenylalanine Compound Having Nitrogen Heterocyclic Link, Pharmaceutical Composition Thereof, Preparation Method Therefor, and Use Thereof. WO2014169817. 2014.
   Google Scholar
• NCT02444910. Effects of KDT501 on metabolic features in insulin resistant subjects [Internet]. 2015 [cited 2016 Apr 20]. Available from: www.ClincialTrials.gov
   Google Scholar
• Konda VR, Desai A, Darland G, et al. KDT501, a derivative from hops, normalizes glucose metabolism and body weight in rodent models of diabetes. Plos One. 2014;9:e87848.
   PubMed Web of Science ®Google Scholar
• Suzuki T, Igari S-I, Hirasawa A, et al. Identification of G protein-coupled receptor 120-selective agonists derived from PPAR gamma agonists. J Med Chem. 2008;51:7640–7644.
   PubMed Web of Science ®Google Scholar
• Tremblay H, Hara T, Hirasawa A, et al. Exploring the chemical space of GPR40 and GPR120 with small molecules. 245th American Chemical Society National Meeting; 2013 April 7–11; New Orleans, LA. Abstract MEDI 412.
   Google Scholar
• Shimpukade B, Hudson BD, Hovgaard CK, et al. Discovery of a potent and selective GPR120 agonist. J Med Chem. 2012;55:4511–4515.
   PubMed Web of Science ®Google Scholar
• Kim YK, Park SY, Joo HW, et al. Biaryl Derivatives as GPR120 Agonists. WO2014209034. 2014.
   Google Scholar
• Kim YK, Kim MY, Park SY, et al., Thioaryl Derivatives as GPR120 Agonists. WO2014069963. 2014.
   Google Scholar
• Sui Z, Cai C, Zhang X, GPR120 Agonists for The Treatment of Type II Diabetes. WO2014159054. 2014.
   Google Scholar
• Sui Z, Winters MP, Bicyclic Pyrrole Derivatives Useful as Agonists of GPR120. WO2014149987. 2014.
   Google Scholar
• He X, Zhu X, Yang K, et al., Compounds and methods for modulating G-protein coupled receptors. WO2010008831. 2010.
   Google Scholar
• Shi DF, Song J, Ma J, et al., GPR120 receptor agonists and uses thereof. WO2011159297. 2011.
   Google Scholar
• Hashimoto N, Sasaki Y, Nakama C, et al., Novel phenyl-isoxazol-3-ol derivative. WO2008066131. 2008.
   Google Scholar
• Zhang H, Cheng PTW, Chen S, et al., Oxabicyclo [2.2.2] Acid GPR120 Modulators. WO2014151247. 2014.
   Google Scholar
• Chelliah M, Chu HD, Cox JM, et al., Substituted Spiropiperidinyl Compounds Useful as GPR120 Agonists. WO2014059232. 2014.
   Google Scholar
• Kumar S, Sharma R, Deore VB, et al., Substituted phenyl alkanoic acid compounds as GPR120 agonists and uses thereof. WO2016012965. 2016.
   Google Scholar
• Tsujimoto G, Hirasawa A, Miyata N, et al., G-Protein-Conjugated receptor agonist. WO2008139987. 2008.
   Google Scholar
• Hudson BD, Shimpukade B, Mackenzie AE, et al. The pharmacology of TUG-891, a potent and selective agonist of the free fatty acid receptor 4 (FFA4/GPR120), demonstrates both potential opportunity and possible challenges to therapeutic agonism. Mol Pharmacol. 2013;84:710–725.
   PubMed Web of Science ®Google Scholar
• Hudson BD, Shimpukade B, Milligan G, et al. The molecular basis of ligand interaction at free fatty acid receptor 4 (FFA4/GPR120). J Biol Chem. 2014;289:20345–20358.
   PubMed Web of Science ®Google Scholar
• Liu Z, Hopkins MM, Zhang ZH, et al. Omega-3 fatty acids and other FFA4 agonists inhibit growth factor signaling in human prostate cancer cells. J Pharmacol Exp Ther. 2015;352:380–394.
   PubMed Web of Science ®Google Scholar
• Sparks SM, Chen G, Collins JL, et al. Identification of diarylsulfonamides as agonists of the free fatty acid receptor 4 (FFA4/GPR120). Bioorg Med Chem Lett. 2014;24:3100–3103.
   PubMed Web of Science ®Google Scholar
• Martin C, Passilly-Degrace P, Chevrot M, et al. Lipid-mediated release of GLP-1 by mouse taste buds from circumvallate papillae: putative involvement of GPR120 and impact on taste sensitivity. J Lipid Res. 2012;53:2256–2265.
   PubMed Web of Science ®Google Scholar
• Yoon MK, Park JG, Hong SY, et al. A novel GPR120 agonist, LC540449 reduced steatosis and insulin resistance in the animal model of NAFLD. 64th annual meeting of the American Association for the Study of Liver Diseases (AASLD); 2013 Nov 1–5; Washington, DC. Abstract 685.
   Google Scholar
• Kim BG. LGLS120-A, a potent, selective, and structurally novel GPR120 agonist, provides superior glycemic control to DPP-4 inhibitor in animal model of type 2 diabetes. 75th Annual Meeting of the American Diabetes Association (ADA); 2015 Jun 5–9; Boston, MA. Abstract 1284-P.
   Google Scholar
• Kim BG. Identification of a potent, selective, and structurally novel GPR120 agonist with anti-inflammatory activity. 75th Annual Meeting of the American Diabetes Association (ADA). 2015 Jun 5–9; Boston, MA. Abstract 1242-P.
   Google Scholar
• Shi DF, Song J, Ma J, et al., GPR120 receptor agonists and uses thereof. WO2010080537. 2010.
   Google Scholar
• Shi Y, Cheng PTW, Wang Y, et al., Bicyclo [2.2.1] Acid GPR120 Modulators. WO2014159794. 2014.
   Google Scholar
• Shi Y, Zhang H, Cheng PTW, et al., Bicyclo [2.2.2] Acid GPR120 Modulators. WO2014159802. 2014.
   Google Scholar
• Steneberg P, Rubins N, Bartoov-Shifman R, et al. The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse. Cell Metab. 2005;1:245–258.
   PubMed Web of Science ®Google Scholar
• Brownlie R, Mayers RM, Pierce JA, et al. The long-chain fatty acid receptor, GPR40, and glucolipotoxicity: investigations using GPR40-knockout mice. Biochem Soc Trans. 2008;36:950–954.
   PubMed Web of Science ®Google Scholar
• Nagasumi K, Esaki R, Iwachidow K, et al. Overexpression of GPR40 in pancreatic beta-cells augments glucose-stimulated insulin secretion and improves glucose tolerance in normal and diabetic mice. Diabetes. 2009;58:1067–1076.
   PubMed Web of Science ®Google Scholar
• Waring MJ, Baker DJ, Bennett SNL, et al. Discovery of a series of 2-(pyridinyl)pyrimidines as potent antagonists of GPR40. Medchemcomm. 2015;6:1024–1029.
   Web of Science ®Google Scholar
• Lipinski CA, Lombardo F, Dominy BW, et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2012;64:4–17.
   Web of Science ®Google Scholar
• Christiansen E, Urban C, Grundmann M, et al. Identification of a potent and selective free fatty acid receptor 1 (FFA1/GPR40) agonist with favorable physicochemical and in vitro ADME properties. J Med Chem. 2011;54:6691–6703.
   PubMed Web of Science ®Google Scholar
• Waring MJ. Lipophilicity in drug discovery. Expert Opin Drug Dis. 2010;5:235–248.
   PubMed Web of Science ®Google Scholar
• Keserü GM, Makara GM. The influence of lead discovery strategies on the properties of drug candidates. Nat Rev Drug Discov. 2009;8:203–212.
   PubMed Web of Science ®Google Scholar
• Leeson PD, Young RJ. Molecular property design: does everyone get it? ACS Med Chem Lett. 2015;6:722–725.
   PubMed Web of Science ®Google Scholar
• Wu Q, Wang H, Zhao X, et al. Identification of G-protein-coupled receptor 120 as a tumor-promoting receptor that induces angiogenesis and migration in human colorectal carcinoma. Oncogene. 2013;32:5541–5550.
   PubMed Web of Science ®Google Scholar
• Li A, Yang D, Zhu M, et al. Discovery of novel FFA4 (GPR120) receptor agonists with beta-arrestin2-biased characteristics. Future Med Chem. 2015;7:2429–2437.
   PubMed Web of Science ®Google Scholar
• Skonberg C, Olsen J, Madsen KG, et al. Metabolic activation of carboxylic acids. Expert Opin Drug Metab Toxicol. 2008;4:425–438.
   PubMed Web of Science ®Google Scholar