Design, synthesis, and evaluation of novel and selective G-protein coupled receptor 120 (GPR120) spirocyclic agonists

ACS Medicinal Chemistry Letters

Volumn 8, Issue 1, 2017, Pages 49-54

  Cox, Jason M ^a   Chu, Hong D ^a   Chelliah, Mariappan V ^a,c   Debenham, John S ^a   Eagen, Keith ^a,d   Lan, Ping ^a   Lombardo, Matthew ^a   London, Clare ^a,e   Plotkin, Michael A ^a   Shah, Unmesh ^a,f   Sun, Zhongxiang ^a   Vaccaro, Henry M ^a,g   Venkatraman, Srikanth ^a   Suzuki, Takao ^b   Wang, Nengxue ^b   Ashley, Eric R ^a   Crespo, Alejandro ^a   Madeira, Maria ^a   Leung, Dennis H ^a,h   Alleyne, Candice ^a   Ogawa, Aimie M ^a   Souza, Sarah ^a   Thomas Fowlkes, Brande ^a   Di Salvo, Jerry ^a   Weinglass, Adam ^a   Kirkland, Melissa ^a,i   Pachanski, Michele ^a   Powles, Mary Ann ^a   Tozzo, Effie ^a,j   Akiyama, Taro E ^a   Ujjainwalla, Feroze ^a   Tata, James R ^a   Sinz, Christopher J ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

^b WUXI APPTEC   (China)

^c CENTER FOR DRUG EVALUATION AND RESEARCH   (United States)

^d FREDERICK NATIONAL LABORATORY FOR CANCER RESEARCH   (United States)

^e Dotmatics   (United States)

^f Jones Day   (United States)

^g Genentech ^*

^h GENENTECH INC   (United States)

ⁱ CHARLES RIVER LABORATORIES   (United States)

^j Mitobridge   (United States)

more..

Author keywords

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

Indexed keywords

ANTIDIABETIC AGENT; G PROTEIN COUPLED RECEPTOR 120 AGONIST; GLUCOSE; PIOGLITAZONE; SPIRO COMPOUND; UNCLASSIFIED DRUG;

ANTIDIABETIC ACTIVITY; ARTICLE; DRUG DESIGN; DRUG SCREENING; DRUG STRUCTURE; DRUG SYNTHESIS; HIGH THROUGHPUT SCREENING; HYPERINSULINEMIC-EUGLYCEMIC CLAMP TECHNIQUE; IN VIVO STUDY; NON INSULIN DEPENDENT DIABETES MELLITUS; ORAL GLUCOSE TOLERANCE TEST; PRIORITY JOURNAL; STRUCTURE ACTIVITY RELATION;

EID: 85017434133     PISSN: None     EISSN: 19485875     Source Type: Journal    
DOI: 10.1021/acsmedchemlett.6b00360     Document Type: Article

References (26)

1. IDF Diabetes Atlas, 7th ed.; International Diabetes Federation: Brussels, Belgium, 2016. http://www.diabetesatlas.org.
2. George, C. M.; Bruijn, L. L.; Will, K.; Howard-Thompson, A. Management of Blood Glucose with Noninsulin Therapies in Type 2 Diabetes. Am. Fam. Physician. 2015, 92, 27−34.
3. DeFronzo, R. A.; Triplitt, C. L.; Abdul-Ghani, M.; Cersosimo, E. Novel Agents for the Treatment of Type 2 Diabetes. Diabetes Spectrum 2014, 27, 100−112.
4. Wallia, A.; Molitch, M. E. Insulin Therapy for Type 2 Diabetes Mellitus. JAMA 2014, 311, 2315−2325.
5. Larson, C. J. The Persistent Need for Insulin Sensitizers and other Disease-Modifying Anti-Diabetic Drugs. Expert Rev. Endocrinol. Metab. 2014, 9, 1−3.
6. 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.
7. McCulloch, D. K. Thiazolidinediones in the Treatment of Diabetes Mellitus, 2015. http://www.uptodate.com/contents/thiazolidinediones-in-the-treatment-of-diabetes-mellitus.
8. Grygiel-Gorniak, B. Peroxisome Proliferator-Activated Receptors and Their Ligands: Nutritional and Clinical Implications − a Review. Nutr. J. 2014, 13, 1−10.
9. 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.
10. Liu, H.-D.; Wang, W.; Xu, Z.; Liu, C.; He, D.; Du, L.; Li, M.; Yu, X.; Sun, J. FFA4 Receptor (GPR120): A Hot Target for the Development of Anti-Diabetic Therapies. Eur. J. Pharmacol. 2015, 763, 160−168.
11. Oh, D. Y.; Talukdar, S.; Bae, E. J.; 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, 687−698.
12. Miyauchi, S.; Hirasawa, A.; Ichimura, A.; Hara, T.; Tsujimoto, G. New Frontiers in Gut Nutrient Sensor Research: Free Fatty Acid Sensing in the Gastorintestinal Tract. J. Pharmacol. Sci. 2010, 112, 19− 24.
13. 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.
14. 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. Diabetes Rev. 2015, 11, 107−115.
15. 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.
16. Oh, D. Y.; Walenta, E.; Akiyama, T. E.; Sagakos, W. S.; Lackey, D.; Pessentheiner, A. D.; 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.
17. 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. A.; Finley, M. F.; Johnson, E.; Roussel, T.; Uebele, V. N.; Crespo, A.; Leung, D.; Alleyne, C.; Trusca, D.; Lei, Y.; Howard, A. D.; Ujjainwalla, F.; Tata, J. R.; Sinz, C. J. Discovery of Benzofuran Propanoic Acid GPR120 Agonists: from uHTS Hit to Mechanism-Based Pharmacodynamic Effects. Bioorg. Med. Chem. Lett. 2016, DOI: 10.1016/ j.bmcl.2016.10.054.
18. Due to the complex pharmacology of GPR120 and to gain a better understanding of compound activities, both IP1 and β-Arrestin2 assays were used. See ref 9 for more detail on GPCR pharmacology.
19. 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. WO2014059232 A1.
20. 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.
21. 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.
22. Catterall, W. A. From Ionic Currents to Molecular Mechanisms: The Structure and Function of Voltage-Gated Sodium Channels. Neuron 2000, 26, 13−25.
23. Rendic, S. Summary of Information on Human CYP Enzymes: Human P450 Metabolism Data. Drug Metab. Rev. 2002, 34, 83−448.
24. Andrikopoulos, S.; Blair, A. R.; Deluca, N.; Fam, B. C.; Proietto, J. Evaluating the glucose tolerance test in mice. Am. J. Physiol. Endocrinol. Metab. 2008, 295, E1323−1332.
25. Mathews, D. R.; Hosker, J. P.; Rudenski, A. S.; Naylor, B. A.; Treacher, D. F.; Tuner, R. C. Homeostasis Model Assessment: Insulin Resistance and β-cell Function from Fasting Plasma Glucose and Insulin Concentrations in Man. Diabetologia 1985, 28, 412−419.
26. Azevedo, C. M. G.; Watterson, K. R.; Wargent, E. T.; Hansen, S. V. F.; Hudson, B. D.; Kepczynska, 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.