• 1
    Pearson G., Robinson F., Beers Gibson T., Xu B., Karandikar M., Berman K., Cobb M. (2001) Mitogen-activated protein (MAP) kinase path-ways: regulation and physiological functions. Endocr Rev;22:153183.
  • 2
    Kyriakis J.M., Avruch J. (2001) Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev;81:807869.
  • 3
    Morphy R. (2010) Selectively nonselective kinase inhibition: striking the right balance. J Med Chem;53:14131437.
  • 4
    Scapin G. (2006) Protein kinase inhibition: different approaches to selective inhibitor design. Curr. Drug Targets;7:14431454.
  • 5
    Sundaramurthy P., Gakkhar S., Sowdhamini R. (2009) Analysis of the impact of ERK5, JNK, and P38 kinase cascades on each other: a systems approach. Bioinformation;3:244249.
  • 6
    Hill C.S., Treisman R. (1995) Transcriptional regulation by extracellular signals: mechanisms and specificity. Cell;80:199211.
  • 7
    Goillot E., Raingeaud J., Ranger A., Tepper R.I., Davis R.J., Harlow E., Sanchez I. (1997) Mitogen-activated protein kinase-mediated Fas apoptotic signaling pathway. Proc Natl Acad Sci U S A;94:33023307.
  • 8
    English J.M., Cobb M.H. (2002) Pharmacological inhibitors of MAPK pathways. Trends Pharmacol Sci;23:4045.
  • 9
    Hynes J. Jr, Leftheri K. (2005) Small molecule p38 inhibitors: novel structural features and advances from 2002-2005. Curr Top Med Chem;5:967985.
  • 10
    Wrobleski S.T., Doweyko A.M. (2005) Structural comparison of p38 inhibitor-protein complexes: a review of recent p38 inhibitors having unique binding interactions. Curr Top Med Chem;5:10051016.
  • 11
    Edrakil N., Hemmateenejad B., Miri R., Khoshneviszade M. (2007) QSAR study of phenoxypyrimidine derivatives as potent inhibitors of p38 kinase using different chemometric tools. Chem Biol Drug Des;70:530539.
  • 12
    Pettus L.H., Wurz R.P. (2008) Small molecule p38 MAP kinase inhibitors for the treatment of inflammatory diseases: novel structures and developments during 2006–2008. Curr Top Med Chem;8:14521467.
  • 13
    Lee M.R., Dominguez C. (2005) MAP kinase p38 inhibitors: clinical results and an intimate look at their interactions with p38alpha protein. Curr Med Chem;12:29792994.
  • 14
    Ghose A.K., Herbertz T., Pippin D.A., Salvino J.M., Mallamo J.P. (2008) Knowledge based prediction of ligand binding modes and rational inhibitor design for kinase drug discovery. J Med Chem;51:51495171.
  • 15
    Badrinarayan P., Sastry G.N. (2011) Sequence, structure, and active site analyses of p38 MAP kinase: Exploiting DFG-out conformation as a strategy to design new type II leads. J Chem Inf Model;51:115129.
  • 16
    Filomia F., De Rienzo F., Menziani M.C. (2010) Insights into MAPK p38alpha DFG flip mechanism by accelerated molecular dynamics. Bioorg Med Chem;18:68056812.
  • 17
    Zuccotto F., Ardini E., Casale E., Angiolini M. (2010) Through the gatekeeper door: exploiting the active kinase conformation. J Med Chem;53:26812694.
  • 18
    Wang Z., Canagarajah B.J., Boehm J.C., Kassisà S., Cobb M.H., Young P.R., Meguid S.A., Adams J.L., Goldsmith E.J. (1998) Structural basis of inhibitor selectivity in MAP kinases. Structure;6:11171128.
  • 19
    Adams J.L., Boehm J.C., Gallagher T.F., Kassis S., Webb E.F., Hall R., Sorenson M., Garigipati R., Griswold D.E., Lee J.C. (2001) Pyrimidinylimidazole inhibitors of p38: cyclic N-1 imidazole substituents enhance p38 kinase inhibition and oral activity. Bioorg Med Chem Lett;11:28672870.
  • 20
    Pargellis C., Tong L., Churchill L., Cirillo P.F., Gilmore T., Graham A.G., Grob P.M., Hickey P.M., Hickey E.R., Moss N., Pav S., Regan J. (2002) Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site. Nat Struct Biol;9:268272.
  • 21
    Scapin G., Patel S.B., Lisnock J.M., Becker J.W., LoGrasso P.V. (2003) The structure of JNK3 in complex with small molecule inhibitors: structural basis for potency and selectivity. Chem Biol;10:705712.
  • 22
    Peifer C., Kinkel K., Abadleh M., Schollmeyer D., Laufer S. (2007) From five- to six-membered rings: 3,4-diarylquinolinone as lead for novel p38MAP kinase inhibitors. J Med Chem;50:12131221.
  • 23
    Gaillard P., Etter I.J., Ardissone V., Arkinstall S., Cambet Y., Camps M., Chabert C., Church D., Cirillo R., Gretener D., Halazy S., Nichols A., Szyndralewiez C., Vitte P.A., Gotteland J.P. (2005) Design and synthesis of the first generation of novel potent, selective, and in vivo active (benzothiazol-2-yl)acetonitrile inhibitors of the c-Jun N-terminal kinase. J Med Chem;48:45964607.
  • 24
    Graczyk P.P., Khan A., Bhatia G.S., Palmer V., Medland D., Numata H., Oinuma H. et al. (2005) The neuroprotective action of JNK3 inhibitors based on the 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole scaffold. Bioorg Med Chem Lett;15:46664670.
  • 25
    Swahn B.M., Huerta F., Kallin E., Malmstro J., Weigelt T., Viklund J., Womack P., Xue Y., Ohberg L. (2005) Design and synthesis of 6-anilinoindazoles as selective inhibitors of c-Jun N-terminal kinase-3. Bioorg Med Chem Lett;15:50955099.
  • 26
    Swahn B.M., Xue Y., Arzel E., Kallin E., Magnus A., Plobeck N., Viklund J. (2006) Design and synthesis of 2′-anilino-4,4′-bipyridines as selective inhibitors of c-Jun N-terminal kinase-3. Bioorg Med Chem Lett;16:13971401.
  • 27
    Liu C., Lin J., Pitt S., Zhang R.F., Sack J.S., Kiefer S.E., Kish K. et al. (2008) Benzothiazole based inhibitors of p38alpha MAP kinase. Bioorg Med Chem Lett;18:18741879.
  • 28
    Hynes J. Jr, Wu H., Pitt S., Shen D.R., Zhang R., Schieven G.L., Gillooly K.M. et al. (2008) The discovery of (R)-2-(sec-butylamino)-N-(2-methyl-5-(methylcarbamoyl)phenyl) thiazole-5-carboxamide (BMS-640994)-A potent and efficacious p38alpha MAP kinase inhibitor. Bioorg Med Chem Lett;18:17621767.
  • 29
    Angell R., Aston N.M., Bamborough P., Buckton J.B., Cockerill S., deBoeck S.J., Edwards C.D., Holmes D.S., Jones K.L., Laine D.I., Patel S., Smee P.A., Smith K.J., Somers D.O., Walker A.L. (2008) Biphenyl amide p38 kinase inhibitors 3: improvement of cellular and in vivo activity. Bioorg Med Chem Lett;18:44284432.
  • 30
    Angell R.M., Bamborough P., Cleasby A., Cockerill S.G., Jones K.L., Mooney C.J., Somers D.O., Walker A.L. (2008) Biphenyl amide p38 kinase inhibitors 1: discovery and binding mode. Bioorg Med Chem Lett;18:318323.
  • 31
    Wrobleski S.T., Lin S., Hynes J. Jr, Wu H., Pitt S., Shen D.R., Zhang R. et al. (2008) Design, synthesis, and anti-inflammatory properties of orally active 4-(phenylamino)-pyrrolo[2,1-f][1,2,4]triazine p38alpha mitogen-activated protein kinase inhibitors. Bioorg Med Chem Lett;18:27392744.
  • 32
    Das J., Moquin R.V., Pitt S., Zhang R., Shen D.R., McIntyre K.W., Gillooly K. et al. (2008) Pyrazolo-pyrimidines: a novel heterocyclic scaffold for potent and selective p38 alpha inhibitors. Bioorg Med Chem Lett;18:26522657.
  • 33
    Hynes J. Jr, Dyckman A.J., Lin S., Wrobleski S.T., Wu H., Gillooly K.M., Kanner S.B. et al. (2008) Design, synthesis, and anti-inflammatory properties of orally active 4-(phenylamino)-pyrrolo[2,1-f][1,2,4]triazine p38alpha mitogen-activated protein kinase inhibitors. J Med Chem;51:416.
  • 34
    Murali Dhar T.G., Wrobleski S.T., Lin S., Furch J.A., Nirschl D.S., Fan Y., Todderud G. et al. (2007) Synthesis and SAR of p38alpha MAP kinase inhibitors based on heterobicyclic scaffolds. Bioorg Med Chem Lett;17:50195024.
  • 35
    Herberich B., Cao G.Q., Partha P., Chakrabarti P.P., Falsey J.R., Pettus L., Rzasa R.M. et al. (2008) Discovery of highly selective and potent p38 inhibitors based on a phthalazine scaffold. J Med Chem;51:62716279.
  • 36
    Brooks B.R., Bruccoleri R.E., Olafson B.D., States D.J., Swaminathan S., Karplus M. (1983) CHARMM: a program for macromolecular energy, minimization, and dynamics calculations. J Comp Chem;4:187217.
  • 37
    Berman H.M., Westbrook J., Feng Z., Gilliland G., Bhat T.N., Weissig H., Shindyalov I.N., Bourne P.E. (2000) The Protein Data Bank. Nucleic Acids Res;28:235242.
  • 38
    Hans C., Rattle A. (1983) A “velocity” version of the shake algorithm for molecular dynamics calculations. J Comp Phys;52:2434.
  • 39
    Smilde A., Bro R., Geladi P. (2004) Multi-way analysis. Application in the Chemical Sciences. New York: Wiley & Sons, 2004.