The development of new bicyclic pyrazole-based cytokine synthesis inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 14, Issue 19, 2004, Pages 4945-4948

  Townes, Jennifer A ^a   Golebiowski, Adam ^a   Clark, Michael P ^a   Laufersweiler, Matthew J ^a   Brugel, Todd A ^a   Sabat, Mark ^a   Bookland, Roger G ^a   Laughlin, Steve K ^a   VanRens, John C ^a   De, Biswanath ^a   Hsieh, Lily C ^a   Xu, Susan C ^a   Janusz, Michael J ^a   Walter, Richard L ^a  

^a PROCTER AND GAMBLE PHARMACEUTICALS   (United States)

Author keywords

Anti inflammatory; Bicyclic pyrazole; p38; TNF

Indexed keywords

4 (4 FLUOROPHENYL) 2 (4 METHYLSULFINYLPHENYL) 5 (4 PYRIDYL)IMIDAZOLE; 5 PYRIMIDANE; BICYCLO COMPOUND; HETEROCYCLIC COMPOUND; LIPOPOLYSACCHARIDE; MITOGEN ACTIVATED PROTEIN KINASE P38; MUTANT PROTEIN; PROTEIN SYNTHESIS INHIBITOR; PYRAZOLE DERIVATIVE; PYRIMIDINE DERIVATIVE; SYNAPTOPHYSIN; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

ARTICLE; CELL ASSAY; CONTROLLED STUDY; CRYSTAL STRUCTURE; CRYSTALLIZATION; CYTOKINE PRODUCTION; DRUG DEVELOPMENT; DRUG STRUCTURE; ENZYME ASSAY; ENZYME ISOLATION; GENE MUTATION; HUMAN; HUMAN CELL; MONOCYTE; STRUCTURE ANALYSIS; X RAY CRYSTALLOGRAPHY;

ENZYME INHIBITORS; HUMANS; LIPOPOLYSACCHARIDES; P38 MITOGEN-ACTIVATED PROTEIN KINASES; PYRAZOLES; STRUCTURE-ACTIVITY RELATIONSHIP; TUMOR NECROSIS FACTOR-ALPHA;

EID: 4444346777     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2004.07.024     Document Type: Article

References (20)

1. For a recent review, see: S. Kumar, J. Boehm, and J.C. Lee Nature Rev. Drug Discovery 2 2003 717 726
2. G.J. Pearce, and I.C. Chikanza Biodrugs 15 2001 139 149
3. L.W. Moreland, S.W. Baumgartner, M.H. Schiff, E.A. Tindall, R.M. Fleisenmann, A.L. Weaver, R.E. Ettlinger, S. Cohen, W.J. Koupman, K. Mohler, M.B. Widmer, and C.M. Blosch N. Engl. J. Med. 337 1997 141 147
4. A. Kaser, O. Ludwiczek, S. Holzmann, A.R. Moschen, G. Weiss, B. Enrich, I. Graziadei, S. Dunzendorfer, C.J. Wiedermann, E. Muerzl, E. Grasl, Z. Jasarevic, N. Romani, F.A. Offner, and H. Tilg J. Clin. Immunol. 24 2004 74 85
5. F.M. Brennan, and M. Feldman Curr. Opin. Immunol. 8 1996 872 877
6. G. Camussi, and E. Lupia Drugs 55 1998 613 620
7. F.M. Brennan, M. Field, C.Q. Chu, M. Feldmann, and R.N. Maini Br. J. Rheumatol. 30 Suppl. 1 1991 76
8. P.F. Jackson, and J.L. Bullington Curr. Topics Med. Chem. 2 2002 1011 1020
9. A.M. Badger, J.N. Bradbeer, B. Votta, J.C. Lee, J.L. Adams, and D.E. Griswold J. Pharmacol. Exp. Ther. 279 1996 1453 1461
10. J.S. Tullis, J.C. VanRens, M.G. Natchus, M.P. Clark, B. De, L.C. Hsieh, and M.J. Janusz Bioorg. Med. Chem. Lett. 13 2003 1665 1668
11. For the synthesis of bicyclic pyrazolones, see: M.P. Clark, S.K. Laughlin, M.J. Laufersweiler, R.G. Bookland, T.A. Brugel, A. Golebiowski, M. Sabat, J.A. Townes, J.C. VanRens, J.F. Djung, M.G. Natchus, B. De, L.C. Hsieh, S.C. Xu, R.L. Walter, M.J. Mekel, and M.J. Janusz J. Med. Chem. 47 2004 2724 2727
12. 12 (Promega Co., Madison, WI) following the 4 h incubation period. No inhibitor-induced cytotoxicity was observed during this assay
13. K.M. Mohler, P.R. Sleath, J.N. Fitzner, D.P. Cerretti, M. Alderson, S.S. Kerwar, D.S. Torrance, C. Otten-Evans, T. Greenstreet, K. Weerawarna, S.R. Kronhelm, M. Petersen, M. Gerhart, C.J. Kozlosky, C.J. March, and R.A. Black Nature 370 1994 218 220
14. J.A. Barltrop, T.C. Owen, A.H. Cory, and J.G. Cory Bioorg. Med. Chem. Lett. 1 1991 611 614
15. 4, 2 mM DTT, and 50μM ATP, in the presence of inhibitor at concentrations of 10,000, 2000, 400, and 80 nM in 96-well microtiter plates (Costar). The substrate ATF2 was used at 50 ng/reaction (coated onto plates by overnight incubation at 4°C). The reaction was carried out at 37°C for 1 h. Phosphorylated ATF2 was detected using a phosphoATF2 (Thr71) specific primary antibody (Cell Signaling), which was then followed by ALP-conjugated goat anti-rabbit IgG (Jackson Immune Research). The OD was taken at 405 nm with a reference at 490 nm
16. 16 X-ray data were collected at beamline 17-BM in the facilities of the Industrial Macromolecular Crystallography Association Collaborative Access Team (IMCA-CAT) at the Advanced Photon Source. These facilities are supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with Illinois Institute of Technology (IIT), executed through IIT's Center for Synchrotron Radiation Research and Instrumentation. Use of the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under Contract No. W-31-109-Eng-38
17. Z. Wang, P.C. Harkins, R.J. Ulevitch, J. Han, M.H. Cobb, and E.J. Goldsmith Proc. Natl. Acad. Sci. U.S.A. 94 1997 2327 2332
18. S. Pav, D.M. Whit, S. Rogers, K.M. Crane, C.L. Cywin, W. Davidson, J. Hopkins, M.L. Brown, C.A. Pargellis, and L. Tong Protein Sci. 6 1997 242 245
19. J. Han, J.D. Lee, L. Bibbs, and R.J. Ulevitch Science 265 1994 808 811
20. K. Godl, J. Wissing, and A. Kurtenbach Proc. Natl. Acad. Sci. U.S.A. 100 2003 15434 15439