GPR40激动剂和拮抗剂的研究进展
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摘要
GPR40是一种G蛋白偶联受体,主要分布于胰岛β细胞中.GPR40激活后能够葡萄糖依赖性的促进胰岛素分泌,降低血糖,所以引起低血糖副作用的风险特别低.因此GPR40有望成为治疗2型糖尿病的新靶点.目前很多公司和科研机构集中开发GPR40激动剂和拮抗剂,但是还没有GPR40激动剂和拮抗剂作为2型糖尿病药物上市.本文通过调研文献和专利总结了GPR40激动剂和GPR40拮抗剂的最新研究进展,希望为新型GPR40激动剂和GPR40拮抗剂的开发提供帮助.
GPR40 is a G protein-coupled receptor predominantly expressed on pancreaticβcells.It amplifies glucose-dependent insulin secretion and GPR40 agonists achieve the initially therapeutic endpoint for the treatment of type 2 diabetes mellitus(T2 DM)without the hypoglycemic risk;therefore,it has attracted widespread attention as a promising antidiabetic target.Herein,we review the latest research progress of GPR40 agonists and GPR40 inhibitors and hope to help the development of novel GPR40 agonists and GPR40 inhibitors.
GPR40 is a G protein-coupled receptor predominantly expressed on pancreaticβcells.It amplifies glucose-dependent insulin secretion and GPR40 agonists achieve the initially therapeutic endpoint for the treatment of type 2 diabetes mellitus(T2 DM)without the hypoglycemic risk;therefore,it has attracted widespread attention as a promising antidiabetic target.Herein,we review the latest research progress of GPR40 agonists and GPR40 inhibitors and hope to help the development of novel GPR40 agonists and GPR40 inhibitors.
引文
[1]Itoh Y,Kawamata Y,Harada M.Free fatty acids regulate insulin secretion from pancreatic b cells through GPR40[J].Nature,2003,1600(2000):2001-2004.
[2]Fukunaga Si,Setoguchi S,Hirasawa A,et al.Monitoring ligand-mediated internalization of G protein-coupled receptor as a novel pharmacological approach[J].Life Sci,2006,80(1):17-23.
[3]Wang J,Wu X,Simonavicius N,et al.Medium-chain fatty acids as ligands for orphan G protein-coupled receptor GPR84[J].J Biol Chem,2006,281(45):34457-34464.
[4]Brown A J,Goldsworthy S M,Barnes A A,et al.The Orphan G protein-coupled receptors GPR41and GPR43are activated by propionate and other short chain carboxylic acids[J].J Biol Chem,2003,278(13):11312-11319.
[5]Bartoov-Shifman R,Ridner G,Bahar K,et al.Regulation of the gene encoding GPR40,a fatty acid receptor expressed selectively in pancreaticβcells[J].J Biol Chem,2007,282(32):23561-23571.
[6]Ji T H,Grossmann M,Ji I.G protein-coupled receptors I Diversity of receptor-ligand interactions[J].J Biol Chem,1998,273(28):17299-17302.
[7]Tomita T,Masuzaki H,Iwakura H,et al.Expression of the gene for a membrane-bound fatty acid receptor in the pancreas and islet cell tumours in humans:evidence for GPR40expression in pancreatic beta cells and implications for insulin secretion[J].Diabetologia,2006,49(5):962-968.
[8]Ferdaoussi M,Bergeron V,Zarrouki B,et al.G protein-coupled receptor(GPR)40-dependent potentiation of insulin secretion in mouse islets is mediated by protein kinase D1[J].Diabetologia,2012,55(10):2682-2692.
[9]Nagasumi K,Esaki R,Iwachidow K,et al.Overexpression of GPR40in pancreaticβ-cells augments glucose-stimulated insulin secretion and improves glucose tolerance in normal and diabetic mice[J].Diabetes,2009,58(5):1067-1076.
[10]Edfalk S,Steneberg P,and Edlund H.Gpr40is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion[J].Diabetes,2008,57(9):2280-2287.
[11]Liou A P,Lu X,Sei Y,et al.The G-protein-coupled receptor GPR40directly mediates long-chain fatty acid?induced secretion of cholecystokinin[J].Gastroenterology,2011,140(3):903-912.
[12]Yonezawa T,Katoh K,and Obara Y.Existence of GPR40functioning in a human breast cancer cell line MCF-7[J].Biochem Bioph Res Co,2004,314(3):805-809.
[13]Swaminath G.Fatty acid binding receptors and their physiological role in type 2diabetes[J].Archiv der Pharmazie,2008,341(12):753-761.
[14]McKeown S C,Corbett D F,Goetz A S,et al.Solid phase synthesis and SAR of small molecule agonists for the GPR40receptor[J].Bioorg Med Chem Lett,2007,17(6):1584-1589.
[15]Garrido D M,Corbett D F,Dwornik K A,et al.Synthesis and activity of small molecule GPR40agonists[J].Bioorg Med Chem Lett,2006,16(7):1840-1845.
[16]Corbett D,Dwornik K,Garrido D,et al.Aminophenylcyclopropyl carboxylic acids and derivatives as agonists to GPR40[P].World:WO2005051890.2005-09-06.
[17]Sasaki S,Kitamura S,Negoro N,et al.Design,Synthesis and Biological Activity of Potent and Orally Available G Protein-Coupled Receptor40Agonists[J].J Med Chem,2011,54(5):1365-1378.
[18]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 40agonists for the treatment of type 2diabetes[J].J Med Chem,2012,55(8):3756-3776.
[19]Christiansen E,Due-Hansen M E,Urban C,et al.Structure activity study of dihydrocinnamic acids and discovery of the potent FFA1(GPR40)agonist TUG-469[J].ACS Med Chem Lett,2010,1(7):345-349.
[20]Christiansen E,Due-hansen M E,Urban C,et al.Free fatty acid receptor 1(FFA1/GPR40)agonists:mesylpropoxy appendage lowers lipophilicity and improves ADME properties[J].J Med Chem,2012,55(14):6624-6628.
[21]Negoro K,Ohnuki K,Kurosaki T,et al.Carboxylic acid derivative[P].World:WO 2008066097.2008-06-05.
[22]Song F,Lu S,Gunnet J,et al.Synthesis and Biological Evaluation of 3-Aryl-3-(4-phenoxy)-propionic Acid as a Novel Series of G ProteinCoupled Receptor 40Agonists[J].J Med Chem,2007,50(12):2807-2817.
[23]Zhou C,Tang C,Chang E,et al.Discovery of 5-aryloxy-2,4-thiazolidinediones as potent GPR40agonists[J].Bioorg Med Chem Lett,2010,20(3):1298-1301.
[24]Walsh S P,Severino A,Zhou C,et al.3-Substituted 3-(4-aryloxyaryl)-propanoic acids as GPR40agonists[J].Bioorg Med Chem Lett,2011,21(11):3390-3394.
[25]Bifu T,Biju P,Blizzard T A,et al.Antidiabetic tricyclic compounds[P].World:WO 2015176640.2015-11-26.
[26]Ma Z,Lin D C,Sharma R,et al.Discovery of the imidazole-derived GPR40agonist AM-3189[J].Bioorg Med Chem Lett,2016,26(1):15-20.
[27]Negoro N,Sasaki S,Ito M,et al.Identification of fused-ring alkanoic acids with improved pharmacokinetic profiles that act as G proteincoupled receptor 40/free fatty acid receptor 1agonists[J].J Med Chem,2012,55(4):1538-1552.
[28]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 1agonist as a glucose-dependent insulinotropic agent[J].J Med Chem,2012,55(8):3960-3974.
[29]Kaku K,Enya K,Nakaya R,et al.Efficacy and safety of fasiglifam(TAK-875),a G protein-coupled receptor 40agonist,in Japanese patients with type 2diabetes inadequately controlled by diet and exercise:a randomized,double-blind,placebo-controlled,phase III trial[J].Diabetes Obes Metab,2015,17(7):675-681.
[30]Hamdouchi C,Kahl S D,Patel Lewis A,et al.The discovery,preclinical,and early clinical development of potent and selective GPR40agonists for the treatment of type 2diabetes mellitus(LY2881835,LY2922083and LY2922470)[J].J Med Chem,2016,59(24):10891-10916.
[31]Li Z,Xu X,Huang W,et al.Free fatty acid receptor 1(FFAR1)as an emerging therapeutic target for type 2diabetes mellitus:recent progress and prevailing challenges[J].Med Res Rev,2018,38(2):381-425.
[32]Wang Y,Liu J,Dransfield P J,et al.Discovery and optimization of potent GPR40full agonists containing tricyclic spirocycles[J].ACS Med Chem Lett,2013,4(6):551-555.
[33]Du X,Dransfield P J,Lin D C,et al.Improving the pharmacokinetics of GPR40/FFA1full agonists[J].ACS Med Chem Lett,2014,5(4):384-389.
[34]Chobanian H,Demong D,Guo Y,et al.Antidiabetic compounds[P].US:US 2015014153.2015-02-03.
[35]Player M,R,Huang H,Meegalla S.Pyrazine gpr40agonists for the treatment of type II diabetes[P].US:US 2015039692.2016-01-14.
[36]Tan C P,Feng Y,Zhou Y P,et al.Selective small-molecule agonists of G protein-coupled receptor 40promote glucose-dependent insulin secretion and reduce blood glucose in mice[J].Diabetes,2008,57(8):2211-2219.
[37]Ge M,Lin S,Yang L,et al.Antidiabetic bicyclic compounds[P].World:WO 2008054674.2008-05-08.
[38]Bharate S B,Rodge A,Joshi R K,et al.Discovery of diacylphloroglucinols as a new class of GPR40(FFAR1)agonists[J].Bioorg Med Chem Lett,2008,18(24):6357-6361.
[39]Meanwell N A.Synopsis of some recent tactical application of bioisosteres in drug design[J].Journal of Medicinal Chemistry,2011,54(8):2529-2591.
[40]Christiansen E,Urban C,Merten N,et al.Discovery of potent and selective agonists for the free fatty acid receptor 1(FFA 1/GPR40),apotential target for the treatment of type II diabetes[J].Diabetologia,2008,1(8):7061-7064.
[41]Christiansen E,Hansen S V F,Urban C,et al.Discovery of TUG-770:a highly potent free fatty acid receptor 1(FFA1/GPR40)agonist for treatment of type 2diabetes[J].ACS Med Chem Lett,2013,4(5):441-445.
[42]Defossa E,Goerlitzer J,Klabunde T,et al.4,5-diphenyl-pyrimidinyl substituted carboxylic acids,method for the production and use thereof as medicaments[P].World:WO 2007131621.2007-11-22.
[43]Ellsworth B A,Ewing W,Jurica E.Pyrrolidine gpr40modulators[P].World:WO 2011044073.2011-04-14.
[44]Tikhonova I G,Sum C S,Neumann S,et al.Discovery of novel agonists and antagonists of the free fatty acid receptor 1(FFAR1)using virtual screening[J].J Med Chem,2008,51(3):625-633.
[45]Steneberg P,Rubins N,Bartoov-Shifman R,et al.The FFA receptor GPR40links hyperinsulinemia,hepatic steatosis,and impaired glucose homeostasis in mouse[J].Cell Metab,2005,1(4):245-258.
[46]Briscoe C P,Peat A J,McKeown S C,et al.Pharmacological regulation of insulin secretion in MIN6cells through the fatty acid receptor GPR40:identification of agonist and antagonist small molecules[J].Brit J Pharmacol,2006,148(5):619-628.
[47]Moodaley R,Smith D M,Tough I R,et al.Agonism of free fatty acid receptors 1and 4generates peptide YY-mediated inhibitory responses in mouse colon[J].Br J Pharmacol,2017,174(23):4508-4522.
[48]Sharma N,Bhagat S,Chundawat T S.Recent advances in development of GPR40modulators(FFA1/FFAR1):an emerging target for type2diabetes[J].Mini Rev Med Chem,2017,17(11):947-958.
[49]Sun P,Wang T,Zhou Y,et al.DC260126:a small-molecule antagonist of GPR40that protects against pancreaticβ-cells dysfunction in db/db mice[J].Plos One,2013,8(6):e66744-e66744.
[50]Syed I,Lee J,Moraes-Vieira P M,et al.Palmitic acid hydroxystearic acids activate GPR40,which is involved in their beneficial effects on glucose homeostasis[J].Cell Metab,2018,27(2):419-427.
[2]Fukunaga Si,Setoguchi S,Hirasawa A,et al.Monitoring ligand-mediated internalization of G protein-coupled receptor as a novel pharmacological approach[J].Life Sci,2006,80(1):17-23.
[3]Wang J,Wu X,Simonavicius N,et al.Medium-chain fatty acids as ligands for orphan G protein-coupled receptor GPR84[J].J Biol Chem,2006,281(45):34457-34464.
[4]Brown A J,Goldsworthy S M,Barnes A A,et al.The Orphan G protein-coupled receptors GPR41and GPR43are activated by propionate and other short chain carboxylic acids[J].J Biol Chem,2003,278(13):11312-11319.
[5]Bartoov-Shifman R,Ridner G,Bahar K,et al.Regulation of the gene encoding GPR40,a fatty acid receptor expressed selectively in pancreaticβcells[J].J Biol Chem,2007,282(32):23561-23571.
[6]Ji T H,Grossmann M,Ji I.G protein-coupled receptors I Diversity of receptor-ligand interactions[J].J Biol Chem,1998,273(28):17299-17302.
[7]Tomita T,Masuzaki H,Iwakura H,et al.Expression of the gene for a membrane-bound fatty acid receptor in the pancreas and islet cell tumours in humans:evidence for GPR40expression in pancreatic beta cells and implications for insulin secretion[J].Diabetologia,2006,49(5):962-968.
[8]Ferdaoussi M,Bergeron V,Zarrouki B,et al.G protein-coupled receptor(GPR)40-dependent potentiation of insulin secretion in mouse islets is mediated by protein kinase D1[J].Diabetologia,2012,55(10):2682-2692.
[9]Nagasumi K,Esaki R,Iwachidow K,et al.Overexpression of GPR40in pancreaticβ-cells augments glucose-stimulated insulin secretion and improves glucose tolerance in normal and diabetic mice[J].Diabetes,2009,58(5):1067-1076.
[10]Edfalk S,Steneberg P,and Edlund H.Gpr40is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion[J].Diabetes,2008,57(9):2280-2287.
[11]Liou A P,Lu X,Sei Y,et al.The G-protein-coupled receptor GPR40directly mediates long-chain fatty acid?induced secretion of cholecystokinin[J].Gastroenterology,2011,140(3):903-912.
[12]Yonezawa T,Katoh K,and Obara Y.Existence of GPR40functioning in a human breast cancer cell line MCF-7[J].Biochem Bioph Res Co,2004,314(3):805-809.
[13]Swaminath G.Fatty acid binding receptors and their physiological role in type 2diabetes[J].Archiv der Pharmazie,2008,341(12):753-761.
[14]McKeown S C,Corbett D F,Goetz A S,et al.Solid phase synthesis and SAR of small molecule agonists for the GPR40receptor[J].Bioorg Med Chem Lett,2007,17(6):1584-1589.
[15]Garrido D M,Corbett D F,Dwornik K A,et al.Synthesis and activity of small molecule GPR40agonists[J].Bioorg Med Chem Lett,2006,16(7):1840-1845.
[16]Corbett D,Dwornik K,Garrido D,et al.Aminophenylcyclopropyl carboxylic acids and derivatives as agonists to GPR40[P].World:WO2005051890.2005-09-06.
[17]Sasaki S,Kitamura S,Negoro N,et al.Design,Synthesis and Biological Activity of Potent and Orally Available G Protein-Coupled Receptor40Agonists[J].J Med Chem,2011,54(5):1365-1378.
[18]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 40agonists for the treatment of type 2diabetes[J].J Med Chem,2012,55(8):3756-3776.
[19]Christiansen E,Due-Hansen M E,Urban C,et al.Structure activity study of dihydrocinnamic acids and discovery of the potent FFA1(GPR40)agonist TUG-469[J].ACS Med Chem Lett,2010,1(7):345-349.
[20]Christiansen E,Due-hansen M E,Urban C,et al.Free fatty acid receptor 1(FFA1/GPR40)agonists:mesylpropoxy appendage lowers lipophilicity and improves ADME properties[J].J Med Chem,2012,55(14):6624-6628.
[21]Negoro K,Ohnuki K,Kurosaki T,et al.Carboxylic acid derivative[P].World:WO 2008066097.2008-06-05.
[22]Song F,Lu S,Gunnet J,et al.Synthesis and Biological Evaluation of 3-Aryl-3-(4-phenoxy)-propionic Acid as a Novel Series of G ProteinCoupled Receptor 40Agonists[J].J Med Chem,2007,50(12):2807-2817.
[23]Zhou C,Tang C,Chang E,et al.Discovery of 5-aryloxy-2,4-thiazolidinediones as potent GPR40agonists[J].Bioorg Med Chem Lett,2010,20(3):1298-1301.
[24]Walsh S P,Severino A,Zhou C,et al.3-Substituted 3-(4-aryloxyaryl)-propanoic acids as GPR40agonists[J].Bioorg Med Chem Lett,2011,21(11):3390-3394.
[25]Bifu T,Biju P,Blizzard T A,et al.Antidiabetic tricyclic compounds[P].World:WO 2015176640.2015-11-26.
[26]Ma Z,Lin D C,Sharma R,et al.Discovery of the imidazole-derived GPR40agonist AM-3189[J].Bioorg Med Chem Lett,2016,26(1):15-20.
[27]Negoro N,Sasaki S,Ito M,et al.Identification of fused-ring alkanoic acids with improved pharmacokinetic profiles that act as G proteincoupled receptor 40/free fatty acid receptor 1agonists[J].J Med Chem,2012,55(4):1538-1552.
[28]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 1agonist as a glucose-dependent insulinotropic agent[J].J Med Chem,2012,55(8):3960-3974.
[29]Kaku K,Enya K,Nakaya R,et al.Efficacy and safety of fasiglifam(TAK-875),a G protein-coupled receptor 40agonist,in Japanese patients with type 2diabetes inadequately controlled by diet and exercise:a randomized,double-blind,placebo-controlled,phase III trial[J].Diabetes Obes Metab,2015,17(7):675-681.
[30]Hamdouchi C,Kahl S D,Patel Lewis A,et al.The discovery,preclinical,and early clinical development of potent and selective GPR40agonists for the treatment of type 2diabetes mellitus(LY2881835,LY2922083and LY2922470)[J].J Med Chem,2016,59(24):10891-10916.
[31]Li Z,Xu X,Huang W,et al.Free fatty acid receptor 1(FFAR1)as an emerging therapeutic target for type 2diabetes mellitus:recent progress and prevailing challenges[J].Med Res Rev,2018,38(2):381-425.
[32]Wang Y,Liu J,Dransfield P J,et al.Discovery and optimization of potent GPR40full agonists containing tricyclic spirocycles[J].ACS Med Chem Lett,2013,4(6):551-555.
[33]Du X,Dransfield P J,Lin D C,et al.Improving the pharmacokinetics of GPR40/FFA1full agonists[J].ACS Med Chem Lett,2014,5(4):384-389.
[34]Chobanian H,Demong D,Guo Y,et al.Antidiabetic compounds[P].US:US 2015014153.2015-02-03.
[35]Player M,R,Huang H,Meegalla S.Pyrazine gpr40agonists for the treatment of type II diabetes[P].US:US 2015039692.2016-01-14.
[36]Tan C P,Feng Y,Zhou Y P,et al.Selective small-molecule agonists of G protein-coupled receptor 40promote glucose-dependent insulin secretion and reduce blood glucose in mice[J].Diabetes,2008,57(8):2211-2219.
[37]Ge M,Lin S,Yang L,et al.Antidiabetic bicyclic compounds[P].World:WO 2008054674.2008-05-08.
[38]Bharate S B,Rodge A,Joshi R K,et al.Discovery of diacylphloroglucinols as a new class of GPR40(FFAR1)agonists[J].Bioorg Med Chem Lett,2008,18(24):6357-6361.
[39]Meanwell N A.Synopsis of some recent tactical application of bioisosteres in drug design[J].Journal of Medicinal Chemistry,2011,54(8):2529-2591.
[40]Christiansen E,Urban C,Merten N,et al.Discovery of potent and selective agonists for the free fatty acid receptor 1(FFA 1/GPR40),apotential target for the treatment of type II diabetes[J].Diabetologia,2008,1(8):7061-7064.
[41]Christiansen E,Hansen S V F,Urban C,et al.Discovery of TUG-770:a highly potent free fatty acid receptor 1(FFA1/GPR40)agonist for treatment of type 2diabetes[J].ACS Med Chem Lett,2013,4(5):441-445.
[42]Defossa E,Goerlitzer J,Klabunde T,et al.4,5-diphenyl-pyrimidinyl substituted carboxylic acids,method for the production and use thereof as medicaments[P].World:WO 2007131621.2007-11-22.
[43]Ellsworth B A,Ewing W,Jurica E.Pyrrolidine gpr40modulators[P].World:WO 2011044073.2011-04-14.
[44]Tikhonova I G,Sum C S,Neumann S,et al.Discovery of novel agonists and antagonists of the free fatty acid receptor 1(FFAR1)using virtual screening[J].J Med Chem,2008,51(3):625-633.
[45]Steneberg P,Rubins N,Bartoov-Shifman R,et al.The FFA receptor GPR40links hyperinsulinemia,hepatic steatosis,and impaired glucose homeostasis in mouse[J].Cell Metab,2005,1(4):245-258.
[46]Briscoe C P,Peat A J,McKeown S C,et al.Pharmacological regulation of insulin secretion in MIN6cells through the fatty acid receptor GPR40:identification of agonist and antagonist small molecules[J].Brit J Pharmacol,2006,148(5):619-628.
[47]Moodaley R,Smith D M,Tough I R,et al.Agonism of free fatty acid receptors 1and 4generates peptide YY-mediated inhibitory responses in mouse colon[J].Br J Pharmacol,2017,174(23):4508-4522.
[48]Sharma N,Bhagat S,Chundawat T S.Recent advances in development of GPR40modulators(FFA1/FFAR1):an emerging target for type2diabetes[J].Mini Rev Med Chem,2017,17(11):947-958.
[49]Sun P,Wang T,Zhou Y,et al.DC260126:a small-molecule antagonist of GPR40that protects against pancreaticβ-cells dysfunction in db/db mice[J].Plos One,2013,8(6):e66744-e66744.
[50]Syed I,Lee J,Moraes-Vieira P M,et al.Palmitic acid hydroxystearic acids activate GPR40,which is involved in their beneficial effects on glucose homeostasis[J].Cell Metab,2018,27(2):419-427.
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