RESUMO
The structure based drug design, synthesis and structure-activity relationship of a series of C6 sulfur linked triazolopyridine based p38 inhibitors are described. The metabolic deficiencies of this series were overcome through changes in the C6 linker from sulfur to methylene, which was predicted by molecular modeling to be bioisosteric. X-ray of the ethylene linked compound 61 confirmed the predicted binding orientation of the scaffold in the p38 enzyme.
Assuntos
Benzamidas/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Triazóis/química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Benzamidas/síntese química , Benzamidas/farmacologia , Sítios de Ligação , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Microssomos Hepáticos/metabolismo , Modelos Químicos , Modelos Moleculares , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Ratos , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Potent, highly selective and orally-bioavailable MMP-13 inhibitors have been identified based upon a (pyridin-4-yl)-2H-tetrazole scaffold. Co-crystal structure analysis revealed that the inhibitors bind at the S(1)(') active site pocket and are not ligands for the catalytic zinc atom. Compound 29b demonstrated reduction of cartilage degradation biomarker (TIINE) levels associated with cartilage protection in a preclinical rat osteoarthritis model.
Assuntos
Inibidores de Metaloproteinases de Matriz , Osteoartrite/tratamento farmacológico , Ácidos Picolínicos/química , Inibidores de Proteases/química , Tetrazóis/química , Administração Oral , Animais , Sítios de Ligação , Cartilagem/efeitos dos fármacos , Cartilagem/metabolismo , Domínio Catalítico , Cristalografia por Raios X , Modelos Animais de Doenças , Descoberta de Drogas , Metaloproteinase 13 da Matriz/metabolismo , Ácidos Picolínicos/síntese química , Ácidos Picolínicos/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Ratos , Tetrazóis/síntese química , Tetrazóis/farmacologia , Zinco/químicaRESUMO
PH-797804 is a diarylpyridinone inhibitor of p38alpha mitogen-activated protein (MAP) kinase derived from a racemic mixture as the more potent atropisomer (aS), first proposed by molecular modeling and subsequently confirmed by experiments. On the basis of structural comparison with a different biaryl pyrazole template and supported by dozens of high-resolution crystal structures of p38alpha inhibitor complexes, PH-797804 is predicted to possess a high level of specificity across the broad human kinase genome. We used a structural bioinformatics approach to identify two selectivity elements encoded by the TXXXG sequence motif on the p38alpha kinase hinge: (i) Thr106 that serves as the gatekeeper to the buried hydrophobic pocket occupied by 2,4-difluorophenyl of PH-797804 and (ii) the bidentate hydrogen bonds formed by the pyridinone moiety with the kinase hinge requiring an induced 180 degrees rotation of the Met109-Gly110 peptide bond. The peptide flip occurs in p38alpha kinase due to the critical glycine residue marked by its conformational flexibility. Kinome-wide sequence mining revealed rare presentation of the selectivity motif. Corroboratively, PH-797804 exhibited exceptionally high specificity against MAP kinases and the related kinases. No cross-reactivity was observed in large panels of kinase screens (selectivity ratio of >500-fold). In cellular assays, PH-797804 demonstrated superior potency and selectivity consistent with the biochemical measurements. PH-797804 has met safety criteria in human phase I studies and is under clinical development for several inflammatory conditions. Understanding the rationale for selectivity at the molecular level helps elucidate the biological function and design of specific p38alpha kinase inhibitors.
Assuntos
Benzamidas/farmacologia , Biologia Computacional , Inibidores de Proteínas Quinases/farmacologia , Pironas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Benzamidas/química , Cristalografia por Raios X , Humanos , Ligação de Hidrogênio , Modelos Moleculares , Estrutura Molecular , Fosforilação , Inibidores de Proteínas Quinases/química , Piridonas , Pironas/química , Especificidade por Substrato , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Matrix metalloproteinase-13 (MMP-13) is a zinc-dependent protease responsible for the cleavage of type II collagen, the major structural protein of articular cartilage. Degradation of this cartilage matrix leads to the development of osteoarthritis. We previously have described highly potent and selective carboxylic acid containing MMP-13 inhibitors; however, nephrotoxicity in preclinical toxicology species precluded development. The accumulation of compound in the kidneys mediated by human organic anion transporter 3 (hOAT3) was hypothesized as a contributing factor for the finding. Herein we report our efforts to optimize the MMP-13 potency and pharmacokinetic properties of non-carboxylic acid leads resulting in the identification of compound 43a lacking the previously observed preclinical toxicology at comparable exposures.
Assuntos
Metaloproteinase 13 da Matriz/efeitos dos fármacos , Inibidores de Metaloproteinases de Matriz/síntese química , Inibidores de Metaloproteinases de Matriz/farmacologia , Osteoartrite/tratamento farmacológico , Pirimidinas/síntese química , Pirimidinas/farmacologia , Tetrazóis/síntese química , Tetrazóis/farmacologia , Animais , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Colagenases/efeitos dos fármacos , Cães , Desenho de Fármacos , Humanos , Rim/metabolismo , Macaca fascicularis , Masculino , Inibidores de Metaloproteinases de Matriz/toxicidade , Modelos Moleculares , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
5(S)-Fluoro-N6-(iminoethyl)-l-lysine (14), an analogue of the potent, selective induced nitric oxide synthase (iNOS) inhibitor iminoethyl-l-lysine (1), was synthesized and found to be a selective iNOS inhibitor.
Assuntos
Lisina/síntese química , Óxido Nítrico Sintase/antagonistas & inibidores , Cristalografia por Raios X , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Lisina/análogos & derivados , Lisina/química , Modelos Moleculares , Óxido Nítrico Sintase/química , Óxido Nítrico Sintase Tipo IIRESUMO
In the literature, the introduction of fluorine into bioactive molecules has been known to enhance the biological activity relative to the parent molecule. Described in this article is the synthesis of 4R-fluoro-L-NIL (12) and 4,4-difluoro-L-NIL (23) as part of our iNOS program. Both 12 and 23 were found to be selective iNOS inhibitors as shown in Table 2 below. Secondarily, methodology to synthesize orthogonally protected 4-fluoro-L-lysine and 4,4-difluoro-L-lysine has been developed.