Discovery of pyridones as oral AMPK direct activators

ACS Medicinal Chemistry Letters

Volumn 4, Issue 7, 2013, Pages 632-636

  Mirguet, Olivier ^a,b   Sautet, Stéphane ^a   Clément, Catherine Anne ^a   Toum, Jéroîme ^a   Donche, Frédéric ^a   Marques, Celine ^a   Rondet, Emilie ^a,c   Pizzonero, Mathieu ^a,c   Beaufils, Benjamin ^a   Dudit, Yann ^a   Huet, Pascal ^a   Trottet, Lionel ^a   Grondin, Pascal ^a   Brusq, Jean Marie ^a   Boursier, Eric ^a   Saintillan, Yannick ^a   Nicodeme, Edwige ^a  

^a GLAXOSMITHKLINE   (France)

^b INSTITUT DE RECHERCHES INTERNATIONALES SERVIER   (France)

^c Galapagos SASU   (France)

Author keywords

AMPK direct activator; P gp substrate; pyridone; type 2 diabetes

Indexed keywords

6,7 DIHYDRO 4 HYDROXY 3 (2' HYDROXY 1,1' BIPHENYL 4 YL) 6 OXOTHIENO[2,3 B]PYRIDINE 5 CARBONITRILE; ELACRIDAR; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; PYRIDONE DERIVATIVE;

AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG SOLUBILITY; DRUG SYNTHESIS; GLUCOSE BLOOD LEVEL; IN VIVO STUDY; LONG TERM CARE; METABOLIC DISORDER; MOUSE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PRIORITY JOURNAL; STRUCTURE ACTIVITY RELATION;

EID: 84880139287     PISSN: None     EISSN: 19485875     Source Type: Journal    
DOI: 10.1021/ml400157g     Document Type: Article

References (18)

1. Hardie, D. G.; Hawley, S. A. AMP-activated protein kinase: the energy charge hypothesis revisited Bioessays 2001, 23, 1112-1119
2. Kemp, B. E.; Stapleton, D.; Campbell, D. J.; Chen, Z. P.; Murthy, S.; Walter, M.; Gupta, A.; Adams, J. J.; Katsis, F.; van Denderen, B.; Jennings, I. G.; Iseli, T.; Michell, B. J.; Witters, L. A. AMP-activated protein kinase, super metabolic regulator Biochem. Soc. Trans. 2003, 31, 162-168
3. Carling, D.; Zammita, V. A.; Hardie, D. G. A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis FEBS Lett. 1987, 223, 217-222
4. Garton, A. J.; Campbell, D. G.; Carling, D.; Hardie, D. G.; Colbran, R. J.; Yeaman, S. J. Phosphorylation of bovine hormone-sensitive lipase by the AMP-activated protein kinase. A possible antilipolytic mechanism Eur. J. Biochem. 1989, 179, 249-254
5. Muoio, D. M.; Seefeld, K.; Witters, L. A.; Coleman, R. A. AMP-activated kinase reciprocally regulates triacylglycerol synthesis and fatty acid oxidation in liver and muscle: evidence that sn-glycerol-3-phosphate acyltransferase is a novel target Biochem. J. 1999, 338, 783-791
6. Saha, A. K.; Schwarsin, A. J.; Roduit, R.; Masse, F.; Kaushik, V.; Tornheim, K.; Prentki, M.; Ruderman, N. B. Activation of malonyl-CoA decarboxylase in rat skeletal muscle by contraction and the AMP-activated protein kinase activator 5-aminoimidazole-4-carboxamide-1-β- d -ribofuranoside J. Biol. Chem. 2000, 275, 24279-24783
7. Musi, N.; Goodyear, L. J. Targeting the AMP-activated protein kinase for the treatment of Type 2 diabetes Curr. Drug Targets: Immune, Endocr. Metab. Disord. 2002, 2, 119-127
8. Lochhead, P. A.; Salt, I. P.; Walker, K. S.; Hardie, D. G.; Sutherland, C. 5-Aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase Diabetes 2000, 49, 896-903
9. Zhou, G.; Myers, R.; Li, Y.; Chen, Y.; Shen, X.; Fenyk-Melody, J.; Wu, M.; Ventre, J.; Doebber, T.; Fujii, N.; Musi, N.; Hirshman, M. F.; Goodyear, L. J.; Moller, D. E. Role of AMP-activated protein kinase in mechanism of metformin action J. Clin. Invest. 2001, 108, 1167-1174
10. Kuhajda, F. P. AMP-activated protein kinase and human cancer: cancer metabolism revisited Int. J. Obesity 2008, 32, S36-S41
11. Sanders, M. J.; Grondin, P. O.; Hegarty, B. D.; Snowden, M. A.; Carling, D. Biochem. J. 2007, 403, 139-148 and references cited therein
12. Zhou, G.; Sebhat, I. K.; Zhang, B. B. AMPK activators: potential therapeutics for metabolic and other diseases Acta Physiol. 2009, 196, 175-190
13. Gomez-Galeno, J. E.; Dang, Q.; Nguyen, T. H.; Boyer, S. H.; Grote, M. P.; Sun, Z.; Chen, M.; Craigo, W. A.; van Poelje, P. D.; MacKenna, D. A.; Cable, E. E.; Rolzin, P. A.; Finn, P. D.; Chi, B.; Linemeyer, D. L.; Hecker, S. J.; Erion, M. D. A potent and selective AMPK activator that inhibits de novo lipogenesis ACS Med. Chem. Lett. 2010, 1, 478-482
14. Cool, B.; Zinker, B.; Chiou, W.; Kifle, L.; Cao, N.; Perham, M.; Dickinson, R.; Adler, A.; Gagne, G.; Lyengar, R.; Zhao, G.; Marsh, K.; Kym, P.; Jung, P.; Camp, H. S.; Frevert, E. Cell Metab. 2006, 3, 403-416
15. Scott, J. W.; van Denderen, B. J.; Jorgensen, S. B.; Honeyman, J. E.; Steinberg, G. R.; Oakhill, J. S.; Iseli, T. J.; Koay, A.; Gooley, P. R.; Stapleton, D.; Kemp, B. E. Thienopyridone drugs are selective activators of AMP-activated protein kinase beta1-containing complexes Chem. Biol. 2008, 15, 1220-1230
16. Mirguet, O.; Bouillot, A.; Daugan, A.; Faucher, N.; Dodic, N.; Sautet, S.; Delannee, D.; Toum, J.; Laroze, A.; Donche, F.; Clement, C.; Nguyen, V.-L.; Pineau, O.; Marques, C.; Lamotte, Y.; Martin, F.; Ajakane, M.; Beaufils, B.; Dudit, Y.; Huet, P.; Trottet, L.; Grondin, P.; Saintillan, Y.; Nicodeme, E. Discovery of oral AMPK direct activators for the treatment of diabetes. Abstracts of Papers, 243rd ACS National Meeting & Exposition, San Diego, CA, United States, 25-29 March 2012; MEDI-189.
17. Mirguet, O. Pyrrolopyridone derivatives as activators of AMPK and their preparation and use in the treatment of diseases. US patent WO2011029855, 2011.
18. Hyafil, F.; Vergely, C.; Du Vignaud, P.; Grand-Perret, T. In vitro and in vivo reversal of multidrug resistance by GF120918, an acridonecarboxamide derivative Cancer Res. 1993, 53, 4595-4602