Discovery of chromane propionic acid analogues as selective agonists of GPR120 with in Vivo activity in rodents

ACS Medicinal Chemistry Letters

Volumn 8, Issue 1, 2017, Pages 96-101

  Adams, Gregory L ^a   Velazquez, Francisco ^a   Jayne, Charles ^a   Shah, Unmesh ^a,c   Miao, Shouwu ^a   Ashley, Eric R ^a   Madeira, Maria ^a   Akiyama, Taro E ^a   Salvo, Jerry Di ^a   Suzuki, Takao ^b   Wang, Nengxue ^b   Truong, Quang ^a   Gilbert, Eric ^a   Zhou, Dan ^a   Verras, Andreas ^a   Kirkland, Melissa ^a,d   Pachanski, Michele ^a   Powles, Maryann ^a   Yin, Wu ^a   Ujjainwalla, Feroze ^a   Venkatraman, Srikanth ^a   Edmondson, Scott D ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

^b WUXI APPTEC   (China)

^c Jones Day   (United States)

^d CHARLES RIVER LABORATORIES   (United States)

Author keywords

Chromane; FFAR4; GPR120; Insulin sensitization; Type 2 diabetes

Indexed keywords

AGENTS AFFECTING PROTEIN METABOLISM; CHROMAN DERIVATIVE; CYTOCHROME P450 2C9; CYTOCHROME P450 2D6; CYTOCHROME P450 3A4; FATTY ACID; G PROTEIN COUPLED RECEPTOR 120; PROPIONIC ACID;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; DRUG DESIGN; DRUG POTENCY; DRUG SYNTHESIS; DRUG TARGETING; ENANTIOMER; GLUCOSE BLOOD LEVEL; IC50; IN VITRO STUDY; IN VIVO STUDY; INSULIN SENSITIVITY; INTRINSIC CLEARANCE; MOUSE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; ORAL GLUCOSE TOLERANCE TEST; PRIORITY JOURNAL; STRUCTURE ANALYSIS;

EID: 85017460521     PISSN: None     EISSN: 19485875     Source Type: Journal    
DOI: 10.1021/acsmedchemlett.6b00394     Document Type: Article

References (28)

1. Zimmet, P.; Alberti, K. G. M. M.; Shaw, J. Global and societal implications of the diabetes epidemic. Nature 2001, 414, 782−787.
2. Hu, F. B. Globalization of Diabetes: the role of diet, lifestyle, and genes. Diabetes Care 2011, 34, 1249−1257.
3. IDF Diabetes Atlas, 3rd ed.; International Diabetes Federation: Brussels, Belgium, 2013. http://www.idf.org/diabetesatlas/5e/theglobal-burden.
4. Donath, M. Y.; Shoelson, S. E. Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol. 2011, 11, 98−107.
5. Amos, A. F.; McCarty, D. J.; Zimmet, P. The Rising Global Burden of Diabetes and its Complications: Estimates and Projections to the Year 2010. Diabetic Med. 1997, 14, S7−S85.
6. Miyauchi, S.; Hirasawa, A.; Iga, T.; Liu, N.; Itsubo, C.; Sadakane, K.; Hara, T.; Tsujimoto, G. Distribution and regulation of protein expression of the free fatty acid receptor GPR120. Naunyn-Schmiedeberg's Arch. Pharmacol. 2009, 379, 427−434.
7. Oh, D. Y.; Talukdar, S.; Bae, E. J.; Imamura, T.; Morinaga, H.; Fan, W. Q.; 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, 687−698.
8. Hirasawa, A.; Tsumaya, K.; Awaji, T.; Katsuma, S.; Adachi, T.; Yamada, M.; Sugimoto, Y.; Miyazaki, S.; Tsujimoto, G. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat. Med. 2005, 11, 90−94.
9. Larson, C. J. The Persistent Need for Insulin Sensitizers and other Disease-Modifying Anti-Diabetic Drugs Exp. Rev. Expert Rev. Endocrinol. Metab. 2014, 9, 1−3.
10. Carpino, P. A.; Hepworth, D. Beyond PPARs and Metformin: New Insulin Sensitizers for the Treatment of Type 2 Diabetes. Annu. Rep. Med. Chem. 2012, 47, 177−192.
11. Talukdar, S.; Olefsky, J. M.; Osborn, O. Targeting GPR120 and other fatty acid-sensing GPCRs ameliorates insulin resistance and inflammatory diseases. Trends Pharmacol. Sci. 2011, 32, 543−550.
12. Zhang, D.; Leung, P. S. Potential roles of GPR120 and its agonists in the management of diabetes. Drug Des., Dev. Ther. 2014, 8, 1013−1027.
13. Liu, H. D.; Wang, W. B.; Xu, Z. G.; Liu, C. H.; He, D. F.; Du, L. P.; Li, M. Y.; Yu, X.; Sun, J. P. FFA4 Receptor (GPR120): A hot target for the development of anti-diabetic therapies. Eur. J. Pharmacol. 2015, 763, 160−168.
14. Azevedo, C. M. G.; Watterson, K. R.; Wargent, E. T.; Hansen, S. V. F.; Hudson, B. D.; Kępczynska, 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, 8868.
15. Friesen, R. W.; Ducharme, Y.; Ball, R. G.; Blouin, M.; Boulet, L.; Cote, B.; Frenette, R.; Girard, M.; Guay, D.; Huang, Z.; Jones, T. R.; Laliberte, F.; Lynch, J. J.; Mancini, J.; Martins, E.; Masson, P.; Muise, E.; Pon, D. J.; Siegel, P. K. S.; Styhler, A.; Tsou, N. N.; Turner, M. J.; Young, R. N.; Girard, Y. Optimization of a Tertiary Alcohol Series of Phosphodiesterase-4 (PDE4) Inhibitors: Structure-Activity Relationship Related to PDE4 Inhibition and Human Ether-a-go-go Related Gene Potassium Channel Binding Affinity. J. Med. Chem. 2003, 46, 2413−2426.
16. Catterall, W. A. From Ionic Currents to Molecular Mechanisms: The Structure and Function of Voltage-Gated Sodium Channels. Neuron 2000, 26, 13−25.
17. 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. Invest. Drugs 2016, 25 (8), 871−890.
18. Rendic, S. Summary of Information on Human CYP Enzymes: Human P450 Metabolism Data. Drug Metab. Rev. 2002, 34, 83−448.
19. Milligan, G.; Shimpukade, B.; Ulven, T.; Hudson, B. D. Complex Pharmacology of Free Fatty Acid Receptors. Chem. Rev. 2016, DOI: 10.1021/acs.chemrev.6b00056.
20. Sekiguchi, H.; Kasubuchi, M.; Hasegawa, S.; Pelisch, N.; Kimura, I.; Ichimura, A. A Novel Antidiabetic Therapy: Free Fatty Acid Receptors as Potential Drug Target Curr. Curr. Diabetes Rev. 2015, 11, 107−115.
21. Mancini, A. D.; Poitout, V. GPR40 Agonists for the Treatment of Type 2 Diabetes: Life after ‘TAKing’ a Hit. Diabetes, Obes. Metab. 2015, 17, 622−629.
22. Oh, D. Y.; Walenta, E.; Akiyama, T. E.; Lagakos, W. S.; Lackey, D.; Pessentheiner, A. R.; Sasik, R.; Hah, N.; Chi, T. J.; Cox, J. M.; Powels, M. A.; Di Salvo, J.; Sinz, C.; Watkins, S. M.; Armando, A. M.; Chung, H.; Evans, R. M.; Quehenberger, O.; McNelis, J.; Bogner-Strauss, J. G.; Olefsky, J. M. A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice. Nat. Med. 2014, 20, 942−949.
23. Chelliah, M.; Chu, H. D.; Cox, J. M.; Debenham, J. S.; Eagen, K.; Lan, P.; London, C.; Plotkin, M. A.; Shah, U.; Sun, Z.; Vaccaro, H. M.; Venkatraman, S. Substituted Spiropiperidinyl Compounds Useful as GPR120 Agonists. PCT Int. Appl. WO2014059232A1.
24. Cox, J. M.; Chu, H. D.; Chelliah, M.; 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.; Crespo, A.; Madeira, M.; Leung, D.; Alleyne, C.; Ogawa, A. M.; Souza, S.; Thomas-Fowlkes, B.; Di Salvo, J.; Weinglass, A.; Kirkland, M.; Pachanski, M.; Powles, M.; 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. 2016, DOI: 10.1021/acsmedchem-lett.6b00360.
25. Lombardo, M.; Bender, K.; London, C.; Kirkland, M.; Mane, J.; Pachanski, M.; Geissler, W.; Cummings, J.; Habulihaz, B.; Akiyama, T. E.; Di Salvo, J.; Madeira, M.; Pols, J.; Powles, M.; Finley, M.; Johnson, E.; Roussel, T.; Uebele, V. N.; Crespo, A.; Leung, D.; Alleyne, C.; Trusca, D.; Lei, Y.; Howard, A. D.; Ujjainwalla, F.; Tata, J.; Sinz, C. J. Discovery of benzofuran propanoic acid GPR120 agonists: from uHTS hit to mechanism-based pharmacodynamic effects. Bioorg. Med. Chem. Lett. 2016, 26, 5724.
26. It should be noted that similar scaffolds were disclosed in a patent application during the preparation of this manuscript. Kim, Y. K.; Park, S. Y.; Joo, H. W.; Choi, E. S. Biaryl Derivative as GPR120 Agonist. PCT Int. Appl. WO2016105118. U.S. Patent US2016/ 168096(A1), 2016.
27. Stone, V. M.; Dhayal, S.; Brocklehurst, K. J.; Lenaghan, C.; Winzell, M. S.; Hammar, M.; Xu, X.; Smith, D. M.; Morgan, N. G. GPR120 (FFAR4) is preferentially expressed in pancreatic delta cells and regulates somatostatin secretion from murine islets of Langerhans. Diabetologia 2014, 57, 1182−1191.
28. Schoemaker, H.; Hicks, P. E.; Langer, S. Z. Calcium Channel Receptor Binding Studies for Diltiazem and its Major Metabolites: Functional Correlation to Inhibition of Portal Vein Myogenic Activity. J. Cardiovasc. Pharmacol. 1987, 9, 173−180.