Intrinsic electrophilicity of the 4-methylsulfonyl-2-pyridone scaffold in glucokinase activators: Role of glutathione-S-transferases and in vivo quantitation of a glutathione conjugate in rats

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 21, 2010, Pages 6262-6267

  Litchfield, John ^a   Sharma, Raman ^a   Atkinson, Karen ^a   Filipski, Kevin J ^a   Wright, Stephen W ^a   Pfefferkorn, Jeffrey A ^a   Tan, Beijing ^a   Kosa, Rachel E ^a   Stevens, Benjamin ^a   Tu, Meihua ^a   Kalgutkar, Amit S ^a  

^a PFIZER INC   (United States)

Author keywords

Cytosol; Electrophile; Glutathione; Glutathione transferase; Microsomes; Pharmacokinetics; Reactive metabolite

Indexed keywords

4 METHYLSULFONYL 2 PYRIDONE; GLUCOKINASE; GLUTATHIONE TRANSFERASE; PYRIDONE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; CATALYST; CHEMICAL REACTION; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG CONJUGATION; DRUG STRUCTURE; ELECTROPHILICITY; HUMAN; IN VITRO STUDY; IN VIVO STUDY; LIVER CYTOSOL; LIVER MICROSOME; NONHUMAN; RAT;

ANIMALS; CATALYSIS; CHROMATOGRAPHY, ION EXCHANGE; CYTOSOL; ENZYME ACTIVATORS; GLUCOKINASE; GLUTATHIONE; GLUTATHIONE TRANSFERASE; HUMANS; INJECTIONS, INTRAVENOUS; MASS SPECTROMETRY; MICROSOMES, LIVER; PYRIDONES; RATS; SPECTROPHOTOMETRY, ULTRAVIOLET; SULFIDES;

RATTUS;

EID: 77957879376     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.08.095     Document Type: Article

References (23)

1. F.P. Guengerich Methods Enzymol. 401 2005 342
2. M.W. Anders Chem. Res. Toxicol. 21 2008 145
3. D.C. Liebler Chem. Res. Toxicol. 21 2008 117
4. A.S. Kalgutkar, I. Gardner, R.S. Obach, C.L. Shaffer, E. Callegari, K.R. Henne, A.E. Mutlib, D.K. Dalvie, J.S. Lee, Y. Nakai, J.P. O'Donnell, J. Boer, and S.P. Harriman Curr. Drug Metab. 6 2005 161
5. C.W. Conroy, H. Schwam, and T.H. Maren Drug Metab. Dispos. 12 1984 614
6. K. Kishida, Y. Akaki, T. Sasabe, C. Yamamoto, and R. Manabe J. Pharm. Sci. 79 1990 638
7. Y. Teffera, A.E. Colletti, J.C. Harmange, L.J. Hollis, B.K. Albrecht, A.A. Boezio, J. Liu, and Z. Zhao Chem. Res. Toxicol. 21 2008 2216
8. K. Inoue, T. Ohe, K. Mori, T. Sagara, Y. Ishii, and M. Chiba Drug Metab. Dispos. 37 2009 1797
9. R.N. Armstrong Chem. Res. Toxicol. 4 1991 131
10. Z. Zhao, K.A. Koeplinger, T. Peterson, R.A. Conradi, P.S. Burton, A. Suarato, R.L. Heinrikson, and A.G. Tomasselli Drug Metab. Dispos. 27 1999 992
11. T.J. Bateman, J.S. Debenham, C. Madsen-Duggan, R.B. Toupence, T.F. Walsh, Q. Truong, S.A. Bradley, G.A. Doss, S. Kumar, and V.B.G. Reddy Drug Metab. Dispos. 38 2010 108
12. J.A. Pfefferkorn, J. Lou, M.L. Minich, K.J. Filipski, M. He, R. Zhou, S. Ahmed, J. Benbow, A. Guzman-Perez, M. Tu, J. Litchfield, R. Sharma, K. Metzler, F. Bourbonais, C. Huang, D.A. Beebe, and P.J. Oates Bioorg. Med. Chem. Lett. 19 2009 3247
13. +).
14. J. Li, M.P. Lynch, K.L. DeMello, S.M. Sakya, H. Cheng, R.J. Rafka, B.S. Bronk, B.H. Jaynes, C. Kilroy, D.W. Mann, M.L. Haven, N.L. Kolosko, C. Petras, S.B. Seibel, and L.A. Lund Bioorg. Med. Chem. Lett. 13 2005 1805
15. G.J. Withbroe, R.A. Singer, and J.E. Sieser Org. Process Res. Dev. 12 2009 480
16. M. Larcheveque, and Y. Petit Tetrahedron Lett. 28 1987 1993
17. M.J. Cryle, N.J. Matovic, and J.J. De Voss Org. Lett. 5 2003 3341
18. 2.
19. J.R. Mitchell, D.J. Jollow, W.Z. Potter, J.R. Gillette, and B.B. Brodie J. Pharmacol. Exp. Ther. 187 1973 211
20. J.R. Mitchell, D.J. Jollow, W.Z. Potter, D.C. Davis, J.R. Gillette, and B.B. Brodie J. Pharmacol. Exp. Ther. 187 1973 185
21. 2 (3.3 mM) and NADPH (1.3 mM) in the presence of GSH (5 mM). In the case of microsomal and cytosol incubations, reactions were initiated with the addition of the biological matrix (microsomes or cytosol). Control incubations were run in parallel in the absence of NADPH and/or GSH. All incubations were conducted in a shaking water bath maintained at 37 °C open to the air. After 60 min, the incubations were terminated by addition of ice-cold acetonitrile containing 0.1% formic acid, mixed vigorously, and the precipitated materials were removed by spinning in a centrifuge (3000g) for 5 min. Aliquots of the supernatants were analyzed for metabolite formation by LC-MS/MS. The HPLC system consisted of an Accela quaternary solvent delivery pump and autoinjector, a Surveyor PDA Plus photodiode array detector (Thermo Electron Corporation, Waltham, MA). Chromatography was performed on a Phenomenex, Synergy RP column, 150 × 4.6 mm, 5 μm (Phenomenex, Torrance, CA). LC analysis was performed at a constant flow rate of 1000 μl/min using a binary solvent system: Solvent A, 5 mM ammonium formate buffer (pH ∼3.0) with 0.1% formic acid and Solvent B, acetonitrile. The initial HPLC gradient system was held at 5% B for 3 min and linearly increased to 80% B in 35 min, followed by a return to initial conditions for column re-equilibration. Post-column flow passed through the PDA detector to provide UV (λ = 200-400 nm) detection prior to being split to the mass spectrometer such that mobile phase was introduced into the electrospray source at a rate of 50 μl/min. The LC system was interfaced to a Thermo Orbitrap mass spectrometer (Thermo Fisher Scientific, Bremen, Germany). Xcalibur software version 2.0 was used to control the HPLC/MS system. Mass spectroscopy analyses were carried out in the positive ion mode using full-scan MS with a mass range of 100-1000 Da. Full scan data and data-dependent MS/MS acquisition on the two most intense ions were collected at 15,000 resolution. All experimental data were acquired using external calibration prior to data acquisition.
22. LUMO energies were calculated with Jaguar module using HF/3-21G level of theory.
23. R.G. Parr, L.V. Szentpaly, and S. Liu J. Am. Chem. Soc. 121 1999 1922