Pyridones as glucokinase activators: Identification of a unique metabolic liability of the 4-sulfonyl-2-pyridone heterocycle

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 12, 2009, Pages 3247-3252

  Pfefferkorn, Jeffrey A ^a   Lou, Jihong ^a   Minich, Martha L ^a   Filipski, Kevin J ^a   He, Mingying ^a   Zhou, Ru ^a   Ahmed, Syed ^a   Benbow, John ^a   Perez, Angel Guzman ^a   Tu, Meihua ^a   Litchfield, John ^a   Sharma, Raman ^a   Metzler, Karen ^a   Bourbonais, Francis ^a   Huang, Cong ^a   Beebe, David A ^a   Oates, Peter J ^a  

^a PFIZER INC   (United States)

Author keywords

Diabetes; Enzyme activation; Glucokinase; Pyridone; Reactive metabolite

Indexed keywords

2 PYRIDONE DERIVATIVE; 4 SULFONYL 2 PYRIDONE DERIVATIVE; GLUCOKINASE; GLUCOSE; GLUTATHIONE; HETEROCYCLIC COMPOUND; INSULIN; PYRIDONE DERIVATIVE; SULFONE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; DISTRIBUTION VOLUME; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG CONJUGATION; DRUG HALF LIFE; DRUG METABOLISM; DRUG POTENCY; DRUG SCREENING; DRUG SYNTHESIS; DRUG TRANSFORMATION; GLUCOSE BLOOD LEVEL; HUMAN; IN VITRO STUDY; INSULIN RELEASE; NONHUMAN; RAT; STEREOSPECIFICITY; STRUCTURE ACTIVITY RELATION;

ANIMALS; BLOOD GLUCOSE; ENZYME ACTIVATION; GLUCOKINASE; GLUTATHIONE; HUMANS; HYPOGLYCEMIC AGENTS; MICROSOMES, LIVER; PYRIDONES; RATS; RATS, SPRAGUE-DAWLEY; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 65749097886     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.04.107     Document Type: Article

References (42)

1. Zimmet P., Alberti K.G., and Shaw J. Nature 414 (2001) 782
2. Wild S., Roglic G., Green A., Sicree R., and King H. Diabetes Care 27 (2004) 1047
3. Saltiel A.R., and Kahn C.R. Nature 14 (2001) 799
4. Xu J. IDrugs 7 (2004) 249
5. Nathan D.M. N. Eng. J. Med. 347 (2002) 1342
6. Mona A., and Smith R.E.Y. Nat. Rev. Drug Disc. 6 (2007) 777
7. For recent reviews, see:. Grimsby J., Berthel S.J., and Sarabu R. Curr. Topics Med. Chem. 8 (2008) 1524
8. Coghlan M., and Leighton B. Exp. Opin. Investig. Drugs 17 (2008) 145
9. Sarabu R., Berthel S.J., Kester R.F., and Tilley J.W. Exp. Opin. Ther. Patents 18 (2008) 759
10. Cardenas M.L. Glucokinase: Its regulation and Role in Liver Metabolism (1995), R.G. Landes Co., Austin pp 21-40
11. Iynedjian, P.B. Glucokinase and Glycemic Disease. From Basics to Novel Therapeutics; Matschinsky, F.M., Magnuson, M.A., Eds.; Karger: Basel, 2004; Vol. 16, p 155.
12. Matschinsky F.M. Diabetes 45 (1996) 223
13. Matschinsky F.M., Glaser B., and Magnuson M.A. Diabetes 47 (1998) 307
14. Dunn-Meynell A.A., Routh V.H., Kang L., Gaspers L., and Levin B.E. Diabetes 51 (2002) 2056
15. Kang L., Dunn-Meynell A.A., Routh V.H., Gaspers L.D., Nagata Y., Nishimura T., Eiki J., Zhang B.B., and Levin B.E. Diabetes 55 (2006) 412
16. Reimann F., and Gribble F.M. Diabetes 51 (2002) 2757
17. For a review, see:. Iynedjian P.B. Cell. Mol. Life Sci. 66 (2009) 27
18. Grimsby J., Sarabu R., Corbett W.L., Haynes N.E., Bizzarro F.T., Coffey J.W., Guertin K.R., Hilliard D.W., Kester R.F., Mahaney P.E., Marcus L., Qi L., Spence C.L., Tengi J., Magnuson M.A., Chu C.A., Dvorozniak M.T., Matschinsky F.M., and Grippo J.F. Science 301 (2003) 370
19. Fyfe M.C., White J.R., Taylor A., Chatfield R., Wargent E., Printz R.L., Sulpice T., McCormack J.G., Procter M.J., Reynet C., Widdowson P.S., and Wong-Kai-In P. Diabetologia 50 (2007) 1277
20. Nishimura, T.; Iino, T.; Nagata, Y.; Eiki, J. WO2003080585.
21. Mitsuya, M.; Kamata, K.; Bamba, M.; Watanabe, H.; Sasaki, Y.; Sasaki, K.; Ohyama, S.; Hosaka, H.; Nagata, Y.; Eiki, J.; Nishimura, T. Bioorg. Med. Chem. 2009, doi: 10.1016/j.bmcl.2009.03.137.
22. McKerrecher D., Allen J.V., Caulkett P.W.R., Donald C.S., Fenwick M.L., Grange E., Johnson K.M., Johnstone C., Jones C.D., Pike K.G., Rayner J.W., and Walker R.P. Bioorg. Med. Chem. Lett. 16 (2006) 2705
23. Zhi, J.; Zhai, S.; Mulligan, M. -E.; Grimsby, J.; Arbet-Engels, C.; Boldrin, M.; Balena, R. Presentation 42, 2008 EASD 44th Annual Meeting, Rome, Italy.
24. Goodnow, R. J.; Le, K. F. WO200183465.
25. Guertin, K. R. F. WO200248106.
26. Cao, S. X.; Feng, J.; Gwaltney, S. L.; Hosfield, D. J.; Skene, R. J.; Stafford, J. A.; Tang, M. US20072811942.
27. A patent application describing structurally similar pyridone-based glucokinase activators has recently published, see: Cheruvallath, Z.; Feng, J.; Guntupalli, P.; Gwaltney, S. L.; Miura, J.; Sabat, M.; Tang, M.; Wang, H. WO2008079787.
28. Minich M.L., Watson I.D., Filipski K.J., and Pfefferkorn J.A. Tetrahedron Lett. 50 (2009) 2094
29. Effenberger F., Maier R., Schoenwaelder K.-H., and Ziegler T. Chem. Ber. 115 (1982) 2766
30. Effenberger F., Ziegler T., and Schoenwaelder K.-H. Chem. Ber. 118 (1985) 741
31. Beszant S., Giannini E., Zanoni G., and Vidari G. Eur. J. Org. Chem. 20 (2003) 3958
32. Basha A., Lipton M., and Weinreb S.M. Tetrahedron Lett. 48 (1977) 4171
33. Menche D., Hassfeld J., Li J., and Rudolph S. J. Am. Chem. Soc. 129 (2007) 6100
34. Biochemical activation assay was conducted using purified recombinant human glucokinase prepared as previously described, see: Ralph, E. C.; Thompson, J.; Sun, S. Biochemistry 2008, 47, 5028. The 6.5 mM glucose concentration was selected to offer an optimal window to measure activation relative to basal enzyme activity. Evaluation of selected activators at higher glucose concentrations confirmed that these analogs continued to activate the enzyme up to 100 mM glucose. An assay protocol is provided in the Supplementary data.
35. Experimental procedures for microsomal and hepatocyte incubations and metabolite identification are provided in the Supplementary data.
36. A review of the literature did not reveal similar examples of glutathione conjugate formation with 4-sulfonyl-2-pyridones. However, glutathione displacement of a sulfonamides have been reported on other heterocycles, for examples see:. Graham S.L., Shepard K.L., Anderson P.S., Baldwin J.J., Best D.B., Christy M.E., Freedman M.B., Gautheron P., Habecker C.N., Hoffman J.M., Lyle P.A., Michelson S.R., Ponticello G.S., Robb C.M., Schwam H., Smith A.M., Smith R.L., Sondey J.M., Strohmaier K.M., Sugrue M.F., and Varga S.L. J. Med. Chem. 32 (1989) 2548
37. Graham S.L., Hoffman J.M., Gautheron P., Michelson S.R., Scholz T.H., Schwam H., Shepard K.L., Smith A.M., Smith R.L., and Sondey J.M. J. Med. Chem. 33 (1990) 749
38. Zhao Z., Koeplinger K.A., Peterson T., Conradi R.A., Burton P.S., Suarato A., Heinrikson R.L., and Tomasselli A.G. Drug Metab. Dispos. 27 (1999) 992
39. Additionally, a glutathione conjugate of a 2-pyridone ring system was reported during biotransformation studies of the cardiotonic agent amrinone; however, in this case, the conjugate occurred at the 6-position of the 2-pyridone rather than the 4-position observed in the current studies. See:. Baker J.F., Chalecki D.P., Benziger P.E., O'Melia S.D., Clemans S.D., and Edelson J. Drug Metab. Dispos. 10 (1982) 168
40. Gericke, R.; Beirer, N.; Wilm, C. WO2003051866.
41. Gijsen, H. J. M.; De Cleyn, M. A. J.; Surkyn, M.; Verbist, B. M. P. WO2008003665.
42. Bantick J.R., Beaton H.G., Cooper S.L., Hill S., Hirst S.C., McInally T., Spencer J., Tinker A.C., and Willis P.A. Bioorg. Med. Chem. Lett. 4 (1994) 121