title: Structure-based design, synthesis and biological evaluation of N-pyrazole, N'-thiazole urea inhibitors of MAP kinase p38α.
abstract: 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.
authors.affiliation: Chemical Genomics Centre of the Max Planck Society, Otto-Hahn-Strasse 15, D-44227 Dortmund, Germany.
authors.forename: Matthäus
authors.initials: M
authors.lastname: Getlik
authors.forename: Christian
authors.initials: C
authors.lastname: Grütter
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Simard
authors.forename: Hoang D
authors.initials: HD
authors.lastname: Nguyen
authors.forename: Armin
authors.initials: A
authors.lastname: Robubi
authors.forename: Beate
authors.initials: B
authors.lastname: Aust
authors.forename: Willem A L
authors.initials: WA
authors.lastname: van Otterlo
authors.forename: Daniel
authors.initials: D
authors.lastname: Rauh
mesh_terms: D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014961:X-Ray Diffraction
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D013844:Thiazoles; D014508:Urea; D048308:Mitogen-Activated Protein Kinase 14