Structure-based design and subsequent optimization of 2-tolyl-(1,2,3-triazol-1-yl-4-carboxamide) inhibitors of p38 MAP kinase

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 11, 2008, Pages 3251-3255

  Cogan, D A ^a   Aungst, R ^b   Breinlinger, E C ^b   Fadra, T ^a   Goldberg, D R ^a   Hao, M H ^a   Kroe, R ^a   Moss, N ^a   Pargellis, C ^a   Qian, K C ^a   Swinamer, A D ^a  

^a BOEHRINGER INGELHEIM PHARMACEUTICALS INC   (United States)

^b ALBANY MOLECULAR RESEARCH INC   (United States)

Author keywords

Inhibitors; MAP kinase; p38; p38 kinase; p38 MAPK; p38a; Structure based drug design; Triazoles

Indexed keywords

2 TOLYL (1,2,3 TRIAZOL 1 YL 4 CARBOXAMIDE) DERIVATIVE; AMIDE; DORAMAPIMOD; MITOGEN ACTIVATED PROTEIN KINASE P38; TRIAZOLE DERIVATIVE;

ARTICLE; AUTOIMMUNE DISEASE; BINDING AFFINITY; COMPUTER AIDED DESIGN; CONTROLLED STUDY; DRUG DESIGN; DRUG IDENTIFICATION; DRUG STRUCTURE; HUMAN; PHYSICAL CHEMISTRY; STRUCTURE ACTIVITY RELATION;

BINDING SITES; COMPUTER-AIDED DESIGN; DRUG DESIGN; ENZYME INHIBITORS; HUMANS; INHIBITORY CONCENTRATION 50; MOLECULAR STRUCTURE; P38 MITOGEN-ACTIVATED PROTEIN KINASES; STRUCTURE-ACTIVITY RELATIONSHIP; TRIAZOLES;

EID: 44149107107     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.04.043     Document Type: Article

References (19)

1. Wagner G., and Laufer S. Med. Res. Rev. 26 (2006) 1
2. Saklatvala J. Curr. Opin. Pharm. 4 (2004) 372
3. Kumar S., Boehm J., and Lee J.C. Nature Rev. Drug Discov. 2 (2003) 717
4. Ono K., and Han J. Cell. Signal. 12 (2000) 1
5. Dominguez C., Powers D.A., and Tamayo N. Curr. Opin. Drug Disc. Dev. 8 (2005) 421
6. Nikas S.N., and Drosos A.A. Curr. Opin. Invest. Drugs 5 (2004) 1205
7. Cirillo P.F., Pargellis C., and Regan J. Curr. Topics Med. Chem. 2 (2002) 1021
8. Klinkhoff A. Drugs 64 (2004) 1267
9. Barry J., and Kirby B. Expert Opin. Biol. Ther. 4 (2004) 975
10. Regan J., Breitfelder S., Cirillo P., Gilmore T., Graham A.G., Hickey E.R., Klaus B., Madwed J., Moriak M., Moss N., Pargellis C.A., Pav S., Proto A., Swinamer A., Tong L., and Torcellini C. J. Med. Chem. 45 (2002) 2994
11. Regan J., Capolino A., Cirillo P.F., Gilmore T., Graham A.G., Hickey E., Kroe R.R., Madwed J., Moriak M., Nelson R., Pargellis C.A., Swinamer A., Torcellini C., Tsang M., and Moss N. J. Med. Chem. 46 (2003) 4676
12. Pargellis C.A., Tong L., Churchill L., Cirillo P., Gilmore T., Graham A.G., Grob P.M., Hickey E.R., Moss N., Pav S., and Regan J. Nat. Struct. Biol. 9 (2002) 268
13. Goldberg D., Hao M.-H., Qian K.C., Swinamer A.D., Gao D.A., Xiong Z., Sarko C., Berry A., Lord J., Magolda R.L., Fadra T., Kroe R.R., Kukulka A., Madwed J.B., Martin L., Pargellis C., Skow D., Song J.J., Tan Z., Torcellini C.A., Zimmitti C.S., Yee N.K., and Moss N. J. Med. Chem. 50 (2007) 4016
14. Wang R., Gao Y., and Lai L. J. Mol. Model 6 (2000) 498
15. SAR at this region will be disclosed in future publications.
16. A 2.8 °C change in thermal denaturation temperature corresponds to approximately a 10-fold change in binding affinity. However, it must be noted that this relationship was developed for pyrazole naphthyl urea-based inhibitors (e.g., BIRB 796), and if the thermodynamics of binding for this class of inhibitors is significantly different, this relationship may be an approximation. Kroe R.R., Regan J., Proto A., Peet G.W., Roy T., Dickert L., Fuschetto N., Pargellis C.A., and Ingraham R.H. J. Med. Chem. 46 (2003) 4669
17. The coordinates have been deposited in the RSCB protein databank (RCSB ID code rcsb047198 and PDB ID code 3CTQ).
18. Fitzgerald C.E., Patel S.B., Becker J.W., Cameron P.M., Zaller D., Pikounis V.B., O'Keefe S.J., and Scapin G. Nature: Struct. Biol. 10 (2003) 764
19. 3, 25% yield).