RESUMO
Optimization of a series of N-1-cycloalkyl-4-aryl-5-(pyrimidin-4-yl)imidazole inhibitors of p38 kinase is reported. Oral administration of inhibitors possessing a cyclohexan-4-ol or piperidin-4-yl group at N-1 in combination with alkoxy, amino(alkyl), phenoxy and anilino substitution at the 2-position of the pyrimidine was found to potently inhibit LPS-induced TNF in mice and rats. The selectivity of these new inhibitors for p38 kinase versus eight other protein kinases is high and in all cases exceeds that of SB 203580.
Assuntos
Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Pirimidinas/química , Administração Oral , Animais , Inibidores das Enzimas do Citocromo P-450 , Inibidores Enzimáticos/química , Imidazóis/química , Lipoxigenase/efeitos dos fármacos , Fígado/enzimologia , Camundongos , Prostaglandina-Endoperóxido Sintases/efeitos dos fármacos , Ratos , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
Members of three classes of pyridinylimidazoles bind with varying affinities to CSBP (p38) kinase which is a member of a stress-induced signal transduction pathway. Based upon SAR and protein homology modeling, the pharmacophore and three potential modes of binding to the enzyme are presented. For a subset of pyridinylimidazoles, binding is shown to correlate with inhibition of CSBP kinase activity, whereas no significant inhibition of PKA, PKC alpha and ERK kinase activity is observed.
Assuntos
Proteínas Quinases Dependentes de Cálcio-Calmodulina/antagonistas & inibidores , Citocinas/biossíntese , Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Estresse Fisiológico/metabolismo , Linhagem Celular , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Humanos , Imidazóis/química , Isoenzimas/antagonistas & inibidores , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Proteína Quinase 3 Ativada por Mitógeno , Modelos Moleculares , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C-alfa , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
A series of N-hydroxyurea derivatives have been prepared and examined as inhibitors of 5-lipoxygenase. Oral activity was established by examining the inhibition of LTB4 biosynthesis in an ex vivo assay in the mouse. The pharmacodynamic performance in the mouse of selected compounds was assessed using an ex vivo LTB4 assay and an adoptive peritoneal anaphylaxis assay at extended pretreat times. Compounds with an extended duration of action were re-examined as the individual enantiomers in the ex vivo assay, and the (S) enantiomer of N-hydroxy-N-[2,3-dihydro-6-(phenylmethoxy)-3-benzofuranyl]urea, (+)-1a (SB 202235), was selected as the compound with the best overall profile. Higher plasma concentrations and longer plasma half-lives were found for (+)-1a relative to its enantiomer in the mouse, monkey, and dog. In vitro metabolic studies in mouse liver microsomes established enantiospecific glucuronidation as a likely mechanism for the observed differences between the enantiomers of 1a. Enantioselective glucuronidation favoring (-)-1a was also found in human liver microsomes.
Assuntos
Benzofuranos/farmacologia , Inibidores de Lipoxigenase , Inibidores de Lipoxigenase/farmacologia , Ureia/análogos & derivados , Animais , Benzofuranos/química , Benzofuranos/farmacocinética , Cromatografia Líquida de Alta Pressão , Cães , Humanos , Inibidores de Lipoxigenase/química , Inibidores de Lipoxigenase/farmacocinética , Macaca fascicularis , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Estereoisomerismo , Ureia/química , Ureia/farmacocinética , Ureia/farmacologiaRESUMO
A series of 1-alkyl- or -aryl-4-aryl-5-pyridinylimidazoles (A) were prepared and tested for their ability to bind to a recently discovered protein kinase termed CSBP and to inhibit lipopolysaccharide (LPS)-stimulated TNF production in mice. The kinase, CSBP, appears to be involved in a signaling cascade initiated by a number of inflammatory stimuli and leading to the biosynthesis of the inflammatory cytokines IL-1 and TNF. Two related imidazole classes (B and C) had previously been reported to bind to CSBP and to inhibit LPS-stimulated human monocyte IL-1 and TNF production. The members of the earlier series exhibited varying degrees of potency as inhibitors of the enzymes of arachidonic acid metabolism, PGHS-1 and 5-LO. Several of the more potent CSBP ligands and TNF biosynthesis inhibitors among the present series of N-1-alkylated imidazoles (A) were tested as inhibitors of PGHS-1 and 5-LO and were found to be weak to inactive as inhibitors of these enzymes. One of the compounds, 9 (SB 210313) which lacked measureable activity as an inhibitor of the enzymes of arachidonate metabolism, and had good potency in the binding and in vivo TNF inhibition assays, was tested for antiarthritic activity in the AA rat model of arthritis. Compound 9 significantly reduced edema and increased bone mineral density in this model.