Citation: Li He, Long Yaqiu. Advances in Small-Molecule GPR40 Agonists for Treatment of Type 2 Diabetes Mellitus[J]. Chinese Journal of Organic Chemistry, ;2016, 36(4): 736-743. doi: 10.6023/cjoc201511011 shu

Advances in Small-Molecule GPR40 Agonists for Treatment of Type 2 Diabetes Mellitus

Li He ,
Long Yaqiu ^,

1.
Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia. Medica, Chinese Academy of Sciences, Shanghai 201203

Corresponding author: Long Yaqiu,
Received Date: 5 November 2015
Available Online: 25 November 2015
Fund Project: 国家自然科学基金(Nos.81325020,81361120410,81321092,81123004)资助项目. (Nos.81325020,81361120410,81321092,81123004)

Currently, the majority of the chemotherapy for type 2 diabetes mellitus (T2DM) functions through glycemic control by administration of oral or injectable hypoglycemic drugs. Though a range of anti-diabetic drugs with different modes of action have been launched, there still remains a significant need for development of effective and highly safe anti-diabetic agents for the increasing diabetic population. GPR40 belongs to the GPCR family and the activation of GPR40 can amplify glucose-stimulated insulin secretion (GSIS). Due to the advantage of minimizing the hypoglycemia risk, GPR40 has drawn more and more attention and emerged as a promising new target for T2DM treatment. Therefore, the recent progress on the structural optimization and further development of small molecule GPR40 agonists as novel treatment for T2DM is reviewed, focused on those under clinical trials or at preclinical stage. A variety of small molecule GPR40 agonists were summarized from the literature and patents based on the pharmacophore model, including the critical phenylpropanoic acid core, the hydrophobic terminus and the linker. The structural features and advantage of different sources of GPR40 agonists were analyzed and highlighted.
- type II diabetes mellitus,
- GPR40,
- agonists,
- glucose-stimulated insulin secretion,
- phenylpropanoic acid
1. [1]
  [1] http://www.idf.org/diabetesatlas/update-2014
2. [2]
  [2] Ahren, B. Nat. Rev. Drug Discovery 2009, 8, 369.
3. [3]
  [3] Itoh, Y.; Kawamata, Y.; Harada, M.; Kobayashi, M.; Fujii, R.; Fukusumi, S.; Ogi, K.; Hosoya, M.; Tanaka, Y.; Uejima, H.; Tanaka, H.; Maruyama, M.; Satoh, R.; Okubo, S.; Kizawa, H.; Komatsu, H.; Matsumura, F.; Noguchi, Y.; Shinobara, T.; Hinuma, S.; Fujisawa, Y.; Fujino, M. Nature 2003, 422, 173.
4. [4]
  [4] Edfalk, S.; Steneberg, P.; Edlund, H. Diabetes 2008, 57, 2280.
5. [5]
  [5] Nakamoto, K.; Nishinaka, T.; Matsumoto, K.; Kasuya, F.; Mankura, M.; Koyama, Y.; Tokuyama, S. Brain Res. 2012, 1432, 74.
6. [6]
  [6] Hauge, M.; Vestmar, M. A.; Husted, A. S.; Ekberg, J. P.; Wright, M. J.; Di Salvo, J.; Weinglass, A. B.; Engelstoft, M. S.; Madsen, A. N.; Luckmann, M.; Miller, M. W.; Trujillo, M. E.; Frimurer, T. M.; Holst, B.; Howard, A. D.; Schwartz, T. W. Mol. Metabolism 2015, 4, 3.
7. [7]
  [7] 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. J. Med. Chem. 2011, 54, 1365.
8. [8]
  [8] Negoro, N.; Sasaki, S.; Ito, M.; Kitamura, S.; Tsujihata, Y.; Ito, R.; Suzuki, M.; Takeuchi, K.; Suzuki, N.; Miyazaki, J.; Santou, T.; Odani, T.; Kanzaki, N.; Funami, M.; Tanaka, T.; Yasuma, T.; Momose, Y. J. Med. Chem. 2012, 55, 1538.
9. [9]
  [9] 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. ACS Med Chem. Lett. 2010, 1, 290.
10. [10]
  [10] Burant, C. F. Diabetes Care 2013, 36, 175.
11. [11]
  [11] http://www.takeda.com/news/2013/20131227_6117.html
12. [12]
  [12] Srivastava, A.; Yano, J.; Hirozane, Y.; Kefala, G.; Gruswitz, F.; Snell, G.; Lane, W.; Ivetac, A.; Aertgeerts, K.; Nguyen, J.; Jennings, A.; Okada, K. Nature 2014, 513, 124.
13. [13]
  [13] Houze, J. B.; Zhu, L. S.; Sun, Y.; Akerman, M.; Qiu, W.; Zhang, A. J.; Sharma, R.; Schmitt, M.; Wang, Y. C.; Liu, J. W.; Liu, J. I. A.; 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. Bioorg. Med. Chem. Lett. 2012, 22, 1267.
14. [14]
  [14] Luo, J.; Swaminath, G.; Brown, S. P.; Zhang, J.; Guo, Q.; Chen, M.; Nguyen, K.; Tran, T.; Miao, L.; Dransfield, P. J.; Vimolratana, M.; Houze, J. B.; Wong, S.; Toteva, M.; Shan, B.; Li, F.; Zhuang, R.; Lin, D. C. H. PLOS One 2012, 7, 46300.
15. [15]
  [15] Liu, J. W.; Wang, Y. C.; Ma, Z. H.; Schmitt, M.; Zhu, L. S.; Brown, S. P.; Dransfield, P. J.; Sun, Y.; Sharma, R.; Guo, Q.; Zhuang, R.; Zhang, J.; Luo, J.; Tonn, G. R.; Wong, S.; Swaminath, G.; Medina, J. C.; Lin, D. C. H.; Houze, J. B. ACS Med. Chem. Lett. 2014, 5, 517.
16. [16]
  [16] Brown, S. P.; Dransfield, P. J.; Vimolratana, M.; Jiao, X. Y.; Zhu, L.; Pattaropong, V.; Sun, Y.; Liu, J. Q.; Luo, J.; Zhang, J.; Wong, S.; Zhuang, R.; Guo, Q.; Li, F.; Medina, J. C.; Swaminath, G.; Lin, D. C. H.; Houze, J. B. ACS Med. Chem. Lett. 2012, 3, 726.
17. [17]
  [17] Wang, Y. C.; Liu, J. W.; Dransfield, P. J.; Zhu, L. S.; Wang, Z. Y.; Du, X. H.; Jiao, X. Y.; Su, Y. L.; Li, A. R.; Brown, S. P.; Kasparian, A.; Vimolratana, M.; Yu, M.; Pattaropong, V.; Houze, J. B.; Swaminath, G.; Tran, T.; Nguyen, K.; Guo, Q.; Zhang, J.; Zhuang, R.; Li, F.; Miao, L.; Bartberger, M. D.; Correll, T. L.; Chow, D.; Wong, S.; Luo, J.; Lin, D. C. H.; Medina, J. C. ACS Med. Chem. Lett. 2013, 4, 551.
18. [18]
  [18] https://clinicaltrials.gov/show/NCT01874366
19. [19]
  [19] Kumar, S.; Sharma, R.; Mahajan, V. A.; Sawargave, S. P. WO 2013128378, 2013 [Chem. Abstr. 2013, 159, 455418].
20. [20]
  [20] Ellsworth, B. A.; Ewing, W. R.; Jurica, E. US 0082165, 2011 [Chem. Abstr.2011, 154, 434695].
21. [21]
  [21] Hernandez, A. S.; Ellsworth, B. A.; Ewing, W. R.; Chen, B. WO 2014078608, 2014 [Chem. Abstr. 2014, 160, 740116].
22. [22]
  [22] Abdel-Magid, A. F. ACS Med. Chem. Lett. 2014, 5, 954.
23. [23]
  [23] Lu, H. J.; Fei, H. B.; Yang, F. L.; Zheng, S. X.; Hu, Q. Y.; Zhang, L.; Yuan, J. J.; Feng, J.; Sun, P. Y.; Dong, Q. Bioorg. Med. Chem. Lett. 2013, 23, 2920.
24. [24]
  [24] 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. J. Med. Chem. 2008, 51, 7061.
25. [25]
  [25] (a) Christiansen, E.; Urban, C.; Grundmann, M.; Due-Hansen, M. E.; Hagesaether, E.; Schmidt, J.; Pardo, L.; Ullrich, S.; Kostenis, E.; Kassack, M.; Ulven, T. J. Med. Chem.2011, 54, 6691.
26. [26]
  (b) 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. J. Med. Chem. 2013, 56, 982.
27. [27]
  [26] Christiansen, E.; Hansen, S. V. F.; Urban, C.; Hudson, B. D.; Wargent, E. T.; Grundmann, M.; Jenkins, L.; Zaibi, M.; Stocker, C. J.; Ullrich, S.; Kostenis, E.; Kassack, M. U.; Milligan, G.; Cawthorne, M. A.; Ulven, T. ACS Med. Chem. Lett. 2013, 4, 441.
28. [28]
  [27] Takano, R.; Yoshida, M.; Inoue, M.; Honda, T.; Nakashima, R.; Matsumoto, K.; Yano, T.; Ogata, T.; Watanabe, N.; Toda, N. Bioorg. Med. Chem. Lett. 2014, 24, 2949.
29. [29]
  [28] Takano, R.; Yoshida, M.; Inoue, M.; Honda, T.; Nakashima, R.; Matsumoto, K.; Yano, T.; Ogata, T.; Watanabe, N.; Hirouchi, M.; Yoneyama, T.; Ito, S.; Toda, N. ACS Med. Chem. Lett. 2015, 6, 266.
30. [30]
  [29] Defossa, E.; Goerlitzer, J.; Klabunde, T.; Drosou, V.; Stengelin, S.; Haschke, G.; Herling, A.; Bartoschek, S. WO 2007131619, 2007 [Chem. Abstr. 2007, 148, 11254].
31. [31]
  [30] Defossa, E.; Follmann, M.; Klabunde, T.; Drosou, V.; Hessler, G.; Stengelin, S.; Haschke, G.; Herling, A.; Bartoschek, S. WO 2007131622, 2007 [Chem. Abstr. 2007, 147, 541859].
32. [32]
  [31] (a) Kell, S.; Deffossa, E.; Dietrich, V.; Stengelin, S.; Herling, A.; Haschke, G.; Klabunde, T. US 20120004166, 2012 [Chem. Abstr. 2012, 156, 122146].
33. [33]
  (b) Kell, S.; Deffossa, E.; Dietrich, V.; Stengelin, S.; Herling, A.; Haschke, G.; Klabunde, T. US 20120004187, 2012 [Chem. Abstr. 2012, 156, 122147].
34. [34]
  [32] Deffossa, E.; Dietrich, V.; Klabunde, T.; Kell, S.; Stengelin, S.; Haschke, G.; Herling, A.; Kuhlmann-Gottke, J.; Bartoschek, S.; Gessler, S.; Dudda, A.; Billen, G.; Ollp, T.; Rieke-Zapp, J. US 20130172248, 2013 [Chem. Abstr. 2013, 159, 181654 ].
35. [35]
  [33] Defossa, E.; Wagner, M. Bioorg. Med. Chem. Lett. 2014, 24, 2991.
36. [36]
  [34] Zhou, C. Y.; Tang, C.; Chang, E.; Ge, M.; Lin, S. N.; Cline, E.; Tan, C. P.; Feng, Y.; Zhou, Y. P.; Eiermann, G. J.; Petrov, A.; Salituro, G.; Meinke, P.; Mosley, R.; Akiyama, T. E.; Einstein, M.; Kumar, S.; Berger, J.; Howard, A. D.; Thornberry, N.; Mills, S. G.; Yang, L. H. Bioorg. Med. Chem. Lett. 2010, 20, 1298.
37. [37]
  [35] Walsh, S. P.; Severino, A.; Zhou, C. Y.; He, J. F.; Liang, G. B.; Tan, C. P.; Cao, J.; Eiermann, G. J.; Xu, L.; Salituro, G.; Howard, A. D.; Mills, S. G.; Yang, L. H. Bioorg. Med. Chem. Lett. 2011, 21, 3390.
38. [38]
  [36] Brockunier, L. L.; Chen, H.; Chobanian, H. R.; Clements, M. J.; Crespo, A.; Demong, D. E.; Guo, Y.; Hagmann, W. K.; Marcantonio, K. M.; Miller, M.; Pio, B.; Plummer, C. W.; Xiao, D. WO 2014130608, 2014 [Chem. Abstr. 2014, 161, 419304].
39. [39]
  [37] Shimada, T.; Ueno, H.; Tsutsumi, K.; Aoyagi, K.; Manabe, T.; Sasaki, S.; Katoh, S. WO 2009054479, 2009 [Chem. Abstr. 2009, 150, 494618].
40. [40]
  [38] Hamdouchi, C.; Lineswala, J. P.; Maiti, P. WO 2011046851, 2011 [Chem. Abstr. 2011, 154, 486226].
41. [41]
  [39] https://clinicaltrials.gov/show/NCT01358981
42. [42]
  [40] Hamdouchi, C. WO 2013025424, 2013 [Chem. Abstr. 2013, 158, 331040].
43. [43]
  [41] Rao, J. M. R.; Arumugam, N.; Ansari, M. M.; Gudla, C.; Pachiyappan, S.; Ramalingam, M.; George, J.; Arul, G. F.; Bommegowda, Y. K.; Angupillai, S. K.; Kottamalai, R.; Jidugu, P.; Rao, D. S. WO 2012011125, 2012 [Chem. Abstr.2012, 156, 202874].
44. [44]
  [42] Gowda, N.; Dandu, A.; Singh, J.; Biswas, S.; Raghav, V.; Lakshmi, M. N.; Shilpa, P. C.; Sunil, V.; Reddy, A.; Sadasivuni, M.; Aparna, K.; Verma, M. K.; Moolemath, Y.; Anup, M. O.; Venkataranganna, M. V.; Somesh, B. P.; Jagannath, M. R. BMC Pharmacol. Toxicol. 2013, 14,28.
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