Getlik M., Grütter C., Simard J.R., Nguyen H.D., Robubi A., Aust B., Van Otterlo W.A.L., Rauh D.
Chemical Genomics Centre of the Max Planck Society, Otto-Hahn-Strasse 15, D-44227 Dortmund, Germany; Fakultät Chemie, Chemische Biologie, Technische Universität Dortmund, Otto-Hahn-Strasse 6, D-44227 Dortmund, Germany; Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Johannesburg, South Africa; Department of Chemistry and Polymer Sciences, Stellenbosch University, Stellenbosch 7600, South Africa
Getlik, M., Chemical Genomics Centre of the Max Planck Society, Otto-Hahn-Strasse 15, D-44227 Dortmund, Germany; Grütter, C., Chemical Genomics Centre of the Max Planck Society, Otto-Hahn-Strasse 15, D-44227 Dortmund, Germany, Fakultät Chemie, Chemische Biologie, Technische Universität Dortmund, Otto-Hahn-Strasse 6, D-44227 Dortmund, Germany; Simard, J.R., Chemical Genomics Centre of the Max Planck Society, Otto-Hahn-Strasse 15, D-44227 Dortmund, Germany; Nguyen, H.D., Chemical Genomics Centre of the Max Planck Society, Otto-Hahn-Strasse 15, D-44227 Dortmund, Germany; Robubi, A., Chemical Genomics Centre of the Max Planck Society, Otto-Hahn-Strasse 15, D-44227 Dortmund, Germany; Aust, B., Chemical Genomics Centre of the Max Planck Society, Otto-Hahn-Strasse 15, D-44227 Dortmund, Germany; Van Otterlo, W.A.L., Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Johannesburg, South Africa, Department of Chemistry and Polymer Sciences, Stellenbosch University, Stellenbosch 7600, South Africa; Rauh, D., Chemical Genomics Centre of the Max Planck Society, Otto-Hahn-Strasse 15, D-44227 Dortmund, Germany, Fakultät Chemie, Chemische Biologie, Technische Universität Dortmund, Otto-Hahn-Strasse 6, D-44227 Dortmund, Germany
In this paper, we present the structure-based design, synthesis and biological activity of N-pyrazole, N′-thiazole-ureas as potent inhibitors of p38α mitogen-activated protein kinase (p38α MAPK). Guided by complex crystal structures, we employed the initially identified N-aryl, N′-thiazole urea scaffold and introduced key structural elements that allowed the formation of novel hydrogen bonding interactions within the allosteric site of p38α, resulting in potent type III inhibitors. [4-(3-tert-Butyl-5-{[(1,3-thiazol-2-ylamino)carbonyl]amino}-1H-pyrazol-1-yl) -phenyl]acetic acid 18c was found to be the most potent compound within this series and inhibited p38α activity with an IC 50 of 135 ± 21 nM. Its closest analog, ethyl [4-(3-tert-butyl-5-{[(1,3-thiazol-2-ylamino) carbonyl]amino}-1H-pyrazol-1-yl)phenyl]acetate 18b, effectively inhibited p38α mediated phosphorylation of the mitogen activated protein kinase activated protein kinase 2 (MK2) in HeLa cells. © 2011 Elsevier Ltd. All rights reserved.
[3 [5 [[[[4 [2 (benzyloxy)ethyl] 1,3 thiazol 2 yl]amino]carbonyl]amino] 3 cyclopentyl 1h pyrazol 1 yl]phenyl]acetic acid; [3 [5 [[[[4 [2 (benzyloxy)ethyl] 1,3 thiazol 2 yl]amino]carbonyl]amino] 3 cyclopropyl 1h pyrazol 1 yl]phenyl]acetic acid; [3 [5 [[[[4 [2 (benzyloxy)ethyl] 1,3 thiazol 2 yl]amino]carbonyl]amino] 3 tert butyl 1h pyrazol 1 yl]phenyl]acetic acid; [4 [3 tert butyl 5 [[(1,3 thiazol 2 ylamino)carbonyl]amino] 1h pyrazol 1 yl]phenyl]acetate; [4 [3 tert butyl 5 [[(1,3 thiazol 2 ylamino)carbonyl]amino] 1h pyrazol 1 yl]phenyl]acetic acid; [4 [5 [[[[4 [2 (benzyloxy)ethyl] 1,3 thiazol 2 yl]amino]carbonyl]amino] 3 cyclopentyl 1h pyrazol 1 yl]phenyl]acetic acid; [4 [5 [[[[4 [2 (benzyloxy)ethyl] 1,3 thiazol 2 yl]amino]carbonyl]amino] 3 tert butyl 1h pyrazol 1 yl]phenyl]acetic acid; ethyl [4 [3 tert butyl 5 [[(1,3 thiazol 2 ylamino)carbonyl]amino] 1h pyrazol 1 yl]phenyl]acetate; mitogen activated protein kinase 14; mitogen activated protein kinase p38 inhibitor; n [3 tert butyl 1 (4 methylphenyl) 1h pyrazol 5 yl] n' (1,3 thiazol 2 yl)urea; n [3 tert butyl 1 (4 methylphenyl) 1h pyrazol 5 yl] n' [4 [2 (4 pyridinylmethoxy)ethyl] 1,3 thiazol 2 yl]urea; n [3 tert butyl 1 (4 methylphenyl) 1h pyrazol 5 yl] n' [4 [2 [(4 fluorobenzyl)oxy]ethyl] 1,3 thiazol 2 yl]urea; n [4 [2 (benzyloxy)ethyl] 1,3 thiazol 2 yl] 3 fluoro 5 (4 morpholinyl)benzamide; n [4 [2 (benzyloxy)ethyl] 1,3 thiazol 2 yl] n' [3 tert butyl 1 (4 methylphenyl) 1h pyrazol 5 yl]urea; n [4 [2 (benzyloxy)ethyl] 1,3 thiazol 2 yl] n' [4 chloro 3 (trifluoromethyl)phenyl]urea; pyrazole derivative; tert butyl 4 (2 hydroxyethyl) 1,3 thiazol 2 ylcarbamate; tert butyl 4 [2 (4 pyridinylmethoxy)ethyl] 1,3 thiazol 2 ylcarbamate; tert butyl 4 [2 (benzyloxy)ethyl] 1,3 thiazol 2 ylcarbamate; tert butyl 4 [2 [(4 fluorobenzyl)oxy]ethyl] 1,3 thiazol 2 ylcarbamate; thiazole derivative; unclassified drug; urea derivative; article; biological activity; controlled study; crystal structure; drug design; drug potency; drug screening; drug structure; drug synthesis; enzyme phosphorylation; female; HeLa cell; human; human cell; pharmacological blocking; Humans; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Mitogen-Activated Protein Kinase 14; Models, Molecular; Protein Kinase Inhibitors; Pyrazoles; Spectrometry, Mass, Electrospray Ionization; Structure-Activity Relationship; Thiazoles; Urea; X-Ray Diffraction