6-Heteroaryl-pyrazolo[3,4-b]pyridines: Potent and selective inhibitors of Glycogen Synthase Kinase-3 (GSK-3)

Bioorganic and Medicinal Chemistry Letters

Volumn 13, Issue 18, 2003, Pages 3059-3062

  Witherington, Jason ^a   Bordas, Vincent ^a   Gaiba, Alessandra ^a   Naylor, Antoinette ^a   Rawlings, Anthony D ^a   Slingsby, Brian P ^a   Smith, David G ^a   Takle, Andrew K ^a   Ward, Robert W ^a  

^a GLAXOSMITHKLINE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

GLYCOGEN SYNTHASE KINASE 3; PHOSPHOTRANSFERASE INHIBITOR; PYRIDINE DERIVATIVE;

ARTICLE; DRUG IDENTIFICATION; DRUG POTENCY; DRUG SELECTIVITY; ENZYME ACTIVITY; ENZYME INHIBITION; STRUCTURE ACTIVITY RELATION;

EID: 0043022153     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(03)00646-2     Document Type: Article

References (21)

1. (a) Leloir L.F., Olavaria S.H., Goldenberg S.H., Carminatti H. Arch. Biochem. Biophys. 81:1959;508.
2. (b) Mandarino L., Wright K., Verity L., Nichols J., Bell J., Kolterman O., Beck-Nielsen H. J. Clin. Invest. 80:1987;655.
3. (c) Roach P. FASEB J. 4:1990;2961
4. (d) Skurat A.V., Roach P.J. Biochem. J. 313:1996;45.
5. (e) Zhang W., DePaoli-Roach A.A., Roach P.J. Arch. Biochem. Biophys. 304:1993;219.
6. (f) Eldar-Finkelmann H., Argast G.M., Foord O., Fischer E.H., Krebs E.G. Proc. Natl. Acad. Sci. U.S.A. 93:1996;10228.
7. (g) DeFronzo R.A., Bonadonna R.C., Ferrannini E. Diabetes Care. 15:1992;318.
8. (h) Thorburn A.W., Gumbiner B., Bulacan F., Wallace P., Henry R.R. J. Clin. Invest. 85:1990;522.
9. (j) Beck-Nielsen H., Vaag A., Damsbo P., Handberg A., Neilsen O.H., Henriksen J.E., Thye-Ronn P. Diabetes Care. 15:1992;418.
10. (k) Bogardus C., Lillioja S., Stone K., Mott D. J. Clin. Invest. 73:1984;1185.
11. (l) Lovestone S., Reynolds C.H., Latimer D., Davis D.R., Anderton B.H., Gallo J.-M., Hanger D., Mulot S., Marquardt B. Curr. Biol. 4:1994;1077.
12. (m) Pap M., Cooper G.M. J. Biol. Chem. 273:1998;19929.
13. (n) Klein P.S., Melton D.A. Proc. Natl. Acad. Sci. U.S.A. 93:1996;8455.
14. Dorronsoro I., Castro A., Martinez A. Expert Opin. Ther. Pat. 12:2002;1527.
15. (a) Witherington, J.; Bordas, V.; Garland, S. L.; Hickey, D. M.; Ife, R. J.; Liddle, J.; Saunders, M.; Smith, D. G.; Ward. R. W. Bioorg. Med. Chem. Lett. In press.
16. (b) Witherington, J.; Bordas, V.; Haigh, D.; Hickey, D. M.; Ife, R. J.; Rawlings, A. D.; Slingsby, B. P.; Smith D. G.; Ward, R. W. Bioorg. Med. Chem. Lett. In press.
17. (c) Witherington, J.; Bordas, V.; Gaiba, A.; Naylor, A.; Rawlings, A. R. ; Slingsby, B. P.; Smith, D. G.; Takle, A. K.; Ward, R. W. Bioorg. Med. Chem. Lett. See preceding paper. doi:10.1016/S0960-894X(03)00645-0.
18. Results are a mean of at least two determinations run in duplicate (n=4) and are given as mean. Mean±SEM is also quoted for compounds of specific interest.
19. Davies S.P., Reddy H., Caivano M., Cohen P. Biochem. J. 351:2000;95.
20. Using microtitre plates, GSK-3 was assayed in 50 mM MOPS buffer, pH 7.0 containing 5% glycerol, 0.01% Tween-20, 7.5 mM 2-mercaptoethanol, 10 mM magnesium actetate, 8 uM substrate peptide (Biotin-KYRRAAVPPSPSLSRHSSPHQ(SP)EDEEE, where (SP) is a pre-phosphorylated serine) and 10 uM [g-33P]-ATP. After incubation for 1 h at room temperature, the reaction was stopped by addition of 50 mM EDTA solution containing Streptavidin coated SPA beads (Amersham) to give a final 0.2 mg of beads per assay well in a 384 microtitre plates were counted in a trilux 1450 microbeta liquid scintillation counter (Wallac).
21. All novel compounds gave satisfactory analytical data in full agreement with their proposed structures.