Design of potent and selective GSK3β inhibitors with acceptable safety profile and pharmacokinetics

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 7, 2010, Pages 2344-2349

  Lesuisse, Dominique ^a   Tiraboschi, Gilles ^a   Krick, Alain ^a   Abecassis, Pierre Yves ^a   Dutruc Rosset, Gilles ^a   Babin, Didier ^a   Halley, Frank ^a   Châtreau, Fabienne ^a   Lachaud, Sylvette ^a   Chevalier, Alain ^a   Quarteronet, Dominique ^a   Burgevin, Marie Claude ^a   Amara, Céline ^a   Bertrand, Philippe ^a   Rooney, Thomas ^a  

^a SANOFI   (France)

Author keywords

Amide hydrolysis; GSK3beta; Kinase; Metabolic stability; Tau phosphorylation

Indexed keywords

CYTOCHROME P450 1A2; GLYCOGEN SYNTHASE; GLYCOGEN SYNTHASE KINASE 3BETA; INDAZOLE DERIVATIVE; PROTEIN KINASE INHIBITOR; TAU PROTEIN;

ALZHEIMER DISEASE; ANIMAL EXPERIMENT; AREA UNDER THE CURVE; ARTICLE; CHEMICAL MODIFICATION; DRUG DESIGN; DRUG HALF LIFE; DRUG POTENCY; DRUG SAFETY; DRUG SELECTIVITY; DRUG STRUCTURE; ENZYME BINDING; ENZYME INHIBITION; HYDROLYSIS; IC 50; LIPOPHILICITY; MOUSE; NONHUMAN; PROTEIN PHOSPHORYLATION; QUANTITATIVE STRUCTURE ACTIVITY RELATION;

ANIMALS; CYTOCHROME P-450 CYP1A2; GLYCOGEN SYNTHASE KINASE 3; HUMANS; MICE; MODELS, MOLECULAR; PROTEIN KINASE INHIBITORS;

EID: 77949657066     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.01.132     Document Type: Article

References (28)

1. Frame S., and Cohen P. Biochem. J. 359 (2001) 1 and references cited therein
2. Flaherty D.B., Soria J.P., Tomasiewicz H.G., and Wood J.G. J. Neurosci. Res. 62 (2000) 463
3. Ferrer J.C., Favre C., Gomis R.R., Fernandez-Novell J.M., Garcia-Rocha M., De La Iglesia N., Cid E., and Guinovart J.J. FEBS Lett. 546 (2003) 127
4. Maccioni R.B., Munoz J.P., and Barbeito L. Arch. Med. Res. 32 (2001) 367
5. Lesuisse D., Dutruc-Rosset G., Tiraboschi G., Dreyer M.K., Maignan S., Chevalier A., Halley F., Bertrand P., Burgevin M.-C., Quarteronet D., and Rooney T. Bioorg. Med. Chem. Lett. 20 (2010) 1985
6. 50 values are calculated by non-linear regression analysis with Excel/XL fit software (IDBS).
7. Murray M. Int. J. Mol. Med. 3 (1999) 227
8. Jalaie M., and Holsworth D.D. Mini-Rev. Med. Chem. 5 (2005) 1083
9. Data from screening panel have to be taken cautiously as false negative results could be obtained with insoluble compounds. This can be seen for instance with compounds 4 and 15.
10. 50 time course variation; CYP1A2 probe substrate 3-cyano-7-ethoxycoumarine (CEC) concentration: 0.002-40 μM. Fluorescent: Ex-410 nm Em-460 nm.
11. The synthesis of the compounds is described in: Dutruc-Rosset, G.; Lesuisse, D.; Rooney, T.; Halley, F. FR 2836915 A1; PCT Patent Publication No. WO2003/078403 A2; Chem. Abstr. 2003, 139, 246027.
12. Lesuisse, D.; Dutruc-Rosset, G.; Halley, F.; Babin, D.; Rooney, T.; Tiraboschi, G. PCT Patent Publication No. WO2004/062662 A1; Chem. Abstr. 2004, 141, 140438.
13. Lesuisse, D.; Dutruc-Rosset, G.; Halley, F.; Babin, D.; Rooney, T. PCT Patent Publication No. WO2004/022544 A; Chem. Abstr. 2004, 140, 253562.
14. Fontana E., Dansette P.M., and Poli S.M. Curr. Drug Metab. 6 (2005) 413
15. Zhou S., Chan S.Y., Goh B.C., Chan E.i., Duan W., Huang M., and McLeod H.L. Clin. Pharmacokinet. 44 (2005) 279
16. Lopez-de-Brinas, E.; Lozano, J. J.; Centeno, N. B.; Segura, J.; Gonzalez, M.; de la Torre, R.; Sanz, F. Molecular Modeling and Prediction of Bioactivity, In Proceedings of the European Symposium on Quantitative Structure-Activity Relationships: Molecular Modeling and Prediction of Bioactivity, 12th ed.; Copenhagen, Denmark, Aug. 23-28, 1998 (2000), Meeting Date 1998, 141-146. Kluwer Academic/Plenum: New York, NY.
17. Lewis D.F., Lake B.G., George S.G., Dickins M., Eddershaw P.J., Tarbit M.H., Beresford A.P., Goldfarb P.S., and Guengerich F.P. Toxicology 139 (1999) 53
18. Lewis D.F.V., Modi S., and Dickins M. Drug Metab. Rev. 34 (2002) 69
19. Riley R.J., Parker A.J., Trigg S., and Manners C.N. Pharm. Res. 18 (2001) 652
20. See for instance:. Korhonen L.E., Rahnasto M., Maehoenen N.J., Wittekindt C., Poso A., Juvonen R.O., and Raunio H. J. Med. Chem. 48 (2005) 3808
21. Lewis D.F.V., Lake B.G., and Dickins M. Xenobiotica 34 (2004) 501
22. 50 are reported in Supplementary data Table 1. Due to the limited number of available data no external validation set could be designed.
23. van de Waterbeemd H., Smith D.A., Beaumont K., and Walker D.K. J. Med. Chem. 44 (2001) 1313
24. Gleeson M.P. J. Med. Chem. 51 (2008) 817
25. Huskey S.-E.W., Doss G.A., Miller R.R., Schoen W.R., and Chiu S.-Hing. Drug Metab. Disposit. 22 (1994) 651
26. Lewis, D. F. V. Guide to Cytochrome P450. Structure and Function, Taylor & Francis (August 2001) p 77.
27. 50 above 50 nM is considered safe versus transcription inhibition.
28. 50 estimation.