In vivo and in vitro SAR of tetracyclic MAPKAP-K2 (MK2) inhibitors. Part i

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 15, 2010, Pages 4715-4718

  Revesz, Laszlo ^a   Schlapbach, Achim ^a   Aichholz, Reiner ^a   Feifel, Roland ^a   Hawtin, Stuart ^a   Heng, Richard ^a   Hiestand, Peter ^a   Jahnke, Wolfgang ^a   Koch, Guido ^a   Kroemer, Markus ^a   Möbitz, Henrik ^a   Scheufler, Clemens ^a   Velcicky, Juraj ^a   Huppertz, Christine ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

Author keywords

Antiinflammatory; In vivo; Inhibition; MAPKAP K2; MK2; Rheumatoid arthritis; TNFa

Indexed keywords

CYCLIC KETONE; ENZYME INHIBITOR; ISOQUINOLINE DERIVATIVE; KETONE DERIVATIVE; LACTAM DERIVATIVE; LIPOPOLYSACCHARIDE; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE 14; PYRROLO[2,3 F]ISOQUINOLINE; STRESS ACTIVATED PROTEIN KINASE; TETRACYCLIC LACTAM; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

ARTICLE; IC 50; IN VITRO STUDY; IN VIVO STUDY; MOUSE; NONHUMAN; PERIPHERAL BLOOD MONONUCLEAR CELL;

ADMINISTRATION, ORAL; AMINO ACIDS; ANIMALS; BINDING SITES; CRYSTALLOGRAPHY, X-RAY; HETEROCYCLIC COMPOUNDS WITH 4 OR MORE RINGS; HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; ISOQUINOLINES; KETONES; LACTAMS; MICE; PROTEIN KINASE INHIBITORS; PROTEIN-SERINE-THREONINE KINASES; PYRROLES; STRUCTURE-ACTIVITY RELATIONSHIP; TUMOR NECROSIS FACTOR-ALPHA;

MUS;

EID: 77955415910     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.04.024     Document Type: Article

References (26)

1. Z. Chen, T.B. Gibson, F. Robinson, L. Silvestro, G. Pearson, B. Xu, A. Wright, C. Vanderbilt, and M.H. Cobb Chem. Rev. 101 2001 2449
2. M. Gaestel Nat. Rev. Mol. Cell. Biol. 7 2006 120
3. A. Kotlyarov, Y. Yannoni, S. Fritz, K. Laass, J.B. Telliez, D. Pitman, L.L. Lin, and M. Gaestel Mol. Cell Biol. 22 2002 4827
4. M. Hegen, M. Gaestel, C.L. Nickerson-Nutter, L.-L. Lin, and J.-B. Telliez J. Immunol. 177 2006 1913
5. D.R. Anderson, S. Hegde, E. Reinhard, L. Gomez, W.F. Vernier, L. Lee, S. Liu, A. Sambandam, P.A. Snider, and L. Masih Bioorg. Med. Chem. Lett. 15 2005 1587
6. J.-P. Wu, J. Wang, A. Abeywardane, D. Andersen, M. Emmanuel, E. Gautschi, D.R. Goldberg, M.A. Kashem, S. Lukas, W. Mao, L. Martin, T. Morwick, N. Moss, C. Pargellis, U.R. Patel, L. Patnaude, G.W. Peet, D. Skow, R.J. Snow, Y. Ward, B. Werneburg, and A. White Bioorg. Med. Chem. Lett. 17 2007 4664
7. J.I. Trujillo, M.J. Meyers, D.R. Anderson, S. Hegde, M.W. Mahoney, W.F. Vernier, I.P. Buchler, K.K. Wu, S. Yang, S.J. Hartmann, and D.B. Reitz Bioorg. Med. Chem. Lett. 17 2007 4657
8. D.R. Goldberg, Y. Choi, D. Cogan, M. Corson, R. DeLeon, A. Gao, L. Gruenbaum, M.H. Hao, D. Joseph, M.A. Kashem, C. Miller, N. Moss, M.R. Netherton, C.P. Pargellis, J. Pelletier, R. Sellati, D. Skow, C. Torcellini, Y.-C. Tseng, J. Wang, R. Wasti, B. Werneburg, J.P. Wu, and Z. Xiong Bioorg. Med. Chem. Lett. 18 2008 938
9. Z. Xiong, D.A. Gao, D.A. Cogan, D.R. Goldberg, M.-H. Hao, N. Moss, E. Pack, C. Pargellis, D. Skow, T. Trieselmann, B. Werneburg, and A. White Bioorg. Med. Chem. Lett. 18 2008 1994
10. D.R. Anderson, M.J. Meyers, W.F. Vernier, M.W. Mahoney, R.G. Kurumbail, N. Caspers, G.I. Poda, J.F. Schindler, D.B. Reitz, and R.J. Mourey J. Med. Chem. 50 2007 2647
11. S. Lin, M. Lombardo, S. Malkani, J.J. Hale, S.G. Mills, K. Chapman, J.E. Thompson, W.X. Zhang, R. Wang, R.M. Cubbon, E.A. O'Neill, S. Luell, E. Carballo-Jane, and L. Yang Bioorg. Med. Chem. Lett. 19 2009 3238
12. D.R. Anderson, M.J. Meyers, R.G. Kurumbail, N. Caspers, G.I. Poda, S.A. Long, B.S. Pierce, M.W. Mahoney, and R.J. Mourey Bioorg. Med. Chem. Lett. 19 2009 4878
13. D.R. Anderson, M.J. Meyers, R.G. Kurumbail, N. Caspers, G.I. Poda, S.A. Long, B.S. Pierce, M.W. Mahoney, R.J. Mourey, and M.D. Parikh Bioorg. Med. Chem. Lett. 19 2009 4882
14. C.M. Harris, A.M. Ericsson, M.A. Argiriadi, C. Barberis, D.W. Borhani, A. Burchat, D.J. Calderwood, G.A. Cunha, R.W. Dixon, K.E. Frank, E.F. Johnson, J. Kamens, S. Kwak, B. Li, K.D. Mullen, D.C. Perron, L. Wang, N. Wishart, X. Wu, X. Zhang, T.R. Zmetra, and R.V. Talanian Bioorg. Med. Chem. Lett. 20 2010 334
15. A. Schlapbach, R. Feifel, S. Hawtin, R. Heng, G. Koch, H. Moebitz, L. Revesz, C. Scheufler, J. Velcicky, R. Waelchli, and C. Huppertz Bioorg. Med. Chem. Lett. 18 2008 6142
16. J. Velcicky, R. Feifel, S. Hawtin, R. Heng, C. Huppertz, G. Koch, M. Kroemer, H. Moebitz, L. Revesz, C. Scheufler, and A. Schlapbach Bioorg. Med. Chem. Lett. 20 2010 1293
17. A. Schlapbach, and C. Huppertz Future Med. Chem. 1 2009 1243 1257
18. H. Iida, Y. Yuasa, and C. Kibayashi Journal. Org. Chem. 45 1980 2938
19. A. Suzuki Pure Appl. Chem. 63 1991 419
20. Revesz, L.; Schlapbach, A.; Waelchli, R. WO 2008025512. Chem. Abstr. 2008, 148, 331658.
21. In-house off-target screen for MK2 inhibitors: ALK, CDK2A, ERK2, EphA4, FGFR-4, FGFR3K, HER1, HER2, INS1R, JAK1, JAK2, KDR, LCK, PDGFRa, PDK1, PKA, PLK1, RET, SYK, cABL, cABLT315, cKIT, cMET, p38a, JNK1, JNK2.
22. P. Gaillard, I. Jeanclaude-Etter, V. Ardissone, S. Arkinstall, Y. Cambet, M. Camps, C. Chabert, D. Church, R. Cirillo, D. Gretener, S. Halazy, A. Nichols, C. Szyndralewiez, P.-A. Vitte, and J.-P. Gotteland Journal. Med. Chem. 48 2005 4596
23. J.F. Hartwig Acc. Chem. Res. 41 2008 1534
24. R.E. Gawley Org. React. 35 1988 1
25. The X-ray coordinates are deposited with RCSB Protein Data Bank, deposition code is 3M42. The protein used in this study is a segment of MK2 containing residues 47-364δ(216-237)G.
26. MK2 inhibitors (100 mg/kg po) were administered to OFI mice (female, 8 weeks old), followed by LPS injection (20 mg/kg) 1 h later. One hour post LPS injection the experiment was terminated and blood withdrawn. Compound blood levels were determined by LC-MS/MS and plasma levels of mouse TNFα determined by ELISA.