RESUMO
A series of N-aryl pyridinone inhibitors of p38 mitogen activated protein (MAP) kinase were designed and prepared based on the screening hit SC-25028 (1) and structural comparisons to VX-745 (5). The focus of the investigation targeted the dependence of potency and metabolic stability on the benzyloxy connectivity, the role of the C-6 position and the substitution pattern on the N-phenyl ring. Further optimization produced the highly selective and potent pyridinones 2 and 3. These inhibitors exhibited activity in both acute and chronic models of inflammation.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Piridonas/síntese química , Piridonas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Masculino , Microssomos Hepáticos/enzimologia , Estrutura Molecular , Piridazinas/química , Piridazinas/farmacologia , Piridonas/química , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
The synthesis and SAR studies of a novel N-aryl pyridinone class of p38 kinase inhibitors are described. Systematic structural modifications to the HTS lead, 5, led to the identification of (-)-4a as a clinical candidate for the treatment of inflammatory diseases. Additionally, the chiral synthesis and properties of (-)-4a are described.
Assuntos
Benzamidas/síntese química , Benzamidas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Pironas/síntese química , Pironas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Benzamidas/química , Modelos Animais de Doenças , Cães , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Macaca fascicularis , Masculino , Estrutura Molecular , Piridonas , Pironas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/química , Proteínas Quinases p38 Ativadas por Mitógeno/farmacologiaRESUMO
The synthesis, structure-activity relationship and modeling of a series of 5-substituted-N-aryl pyridazinone based p38alpha inhibitors are described. In comparing the series to the similar N-aryl pyridinone series, it was found that the pyridazinones maintained a weaker interaction to the p38 enzyme, and therefore showed generally weaker binding than the pyridinones.
Assuntos
Anti-Infecciosos/química , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Piridazinas/química , Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Sítios de Ligação , Simulação por Computador , Descoberta de Drogas , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Piridazinas/síntese química , Piridazinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Starting from an initial HTS screening lead, a novel series of C(5)-substituted diaryl pyrazoles were developed that showed potent inhibition of p38alpha kinase. Key to this outcome was the switch from a pyridyl to pyrimidine at the C(4)-position leading to analogs that were potent in human whole blood based cell assay as well as in a number of animal efficacy models for rheumatoid arthritis. Ultimately, we identified a clinical candidate from this substrate; SD-0006.
Assuntos
Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Domínio Catalítico , Humanos , Modelos Moleculares , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
We recently described a novel series of aminopyridopyrazinones as PDE5 inhibitors. Efforts toward optimization of this series culminated in the identification of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, which possessed an excellent potency and selectivity profile and demonstrated robust in vivo blood pressure lowering in a spontaneously hypertensive rat (SHR) model. Furthermore, this compound is brain penetrant and will be a useful agent for evaluating the therapeutic potential of central inhibition of PDE5. This compound has recently entered clinical trials.
Assuntos
Encéfalo/metabolismo , Inibidores da Fosfodiesterase 5 , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacologia , Pirazinas/síntese química , Pirazinas/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Pressão Sanguínea/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Masculino , Modelos Químicos , Estrutura Molecular , Inibidores de Fosfodiesterase/farmacocinética , Pirazinas/farmacocinética , Piridinas/farmacocinética , Ratos , Ratos Endogâmicos SHR , Ratos Sprague-DawleyRESUMO
The identification and evolution of a series of potent and selective p38 inhibitors is described. p38 inhibitors based on a N-benzyl pyridinone high-throughput screening hit were prepared and their SAR explored. Their design was guided by ligand bound co-crystals of p38alpha. These efforts resulted in the identification of 12r and 19 as orally active inhibitors of p38 with significant efficacy in both acute and chronic models of inflammation.
Assuntos
Anti-Inflamatórios/química , Inibidores de Proteínas Quinases/química , Piridonas/química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Administração Oral , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Descoberta de Drogas , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Microssomos Hepáticos/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Piridonas/síntese química , Piridonas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
We describe efforts to improve the pharmacokinetic profile of the aminopyridopyrazinone class of PDE5 inhibitors. These efforts led to the discovery of 3-[(trans-4-hydroxycyclohexyl)amino]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a potent and selective inhibitor of PDE5 with an excellent PK profile.
Assuntos
Inibidores da Fosfodiesterase 5 , Inibidores de Fosfodiesterase/química , Pirazinas/química , Piridinas/química , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/antagonistas & inibidores , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/metabolismo , Cães , Descoberta de Drogas , Humanos , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacocinética , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Pirazinas/síntese química , Pirazinas/farmacocinética , Piridinas/síntese química , Piridinas/farmacocinética , Ratos , Ratos Endogâmicos SHR , Relação Estrutura-AtividadeRESUMO
Efforts to improve the potency and physical properties of the aminopyridiopyrazinone class of PDE5 inhibitors through modification of the core ring system are described. Five new ring systems are evaluated and features that impart improved potency and improved solubility are delineated.
Assuntos
Aminopiridinas/síntese química , Inibidores da Fosfodiesterase 5 , Inibidores de Fosfodiesterase/síntese química , Pirazinas/síntese química , Administração Oral , Aminopiridinas/farmacologia , Animais , Química Farmacêutica/métodos , GMP Cíclico/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/química , Desenho de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Hipertensão/tratamento farmacológico , Microssomos/efeitos dos fármacos , Modelos Químicos , Inibidores de Fosfodiesterase/farmacologia , Pirazinas/farmacologia , Ratos , Ratos Sprague-Dawley , SolubilidadeRESUMO
A new class of potent and selective PDE5 inhibitors is disclosed. Guided by X-ray crystallographic data, optimization of an HTS lead led to the discovery of a series of 2-aryl, (N8)-alkyl substituted-6-aminosubstituted pyrido[3,2b]pyrazinones which show potent inhibition of the PDE5 enzyme. Synthetic details and some structure-activity relationships are also presented.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/química , Inibidores da Fosfodiesterase 5 , Pirazinas/síntese química , 3',5'-GMP Cíclico Fosfodiesterases , Animais , Domínio Catalítico , Química Farmacêutica/métodos , Cristalografia por Raios X/métodos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/antagonistas & inibidores , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/química , Desenho de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Concentração Inibidora 50 , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/química , Estrutura Terciária de Proteína , Pirazinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
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
The cytotoxic, cyclic heptadepsipeptide, natural product callipeltin B was synthesized on a solid-phase support in 15% overall yield. Comparison of the 1H NMR spectra of three synthetic isomers with those of callipeltin B confirmed the configurational reassignment of its threonine residues as d-allothreonine and the assignment of the configuration of its beta-methoxytyrosine residue as (2R,3R).
Assuntos
Depsipeptídeos/síntese química , Peptídeos Cíclicos/síntese química , Animais , Depsipeptídeos/química , Depsipeptídeos/isolamento & purificação , Peptídeos Cíclicos/química , Peptídeos Cíclicos/isolamento & purificação , Poríferos/química , Conformação ProteicaRESUMO
The absolute stereochemistry of the three unresolved structural components in neamphamide A (1) was determined to be (R)-beta-methoxy-L-tyrosine, (2R,3R,4S)-4-amino-7-guanidino-2,3-dihydroxyheptanoic acid, and (2R,3R,4R)-3-hydroxy-2,4,6-trimethylheptanoic acid. Stereochemical assignments were made by chemical degradation of 1, derivatization of the resulting products, and then spectroscopic and chromatographic comparison of the derivatives with synthetically prepared standards. Using the same analytical protocol developed for 1, the beta-methoxytyrosine residue in papuamide B (2) was found to be (R)-beta-methoxy-D-tyrosine. This represents a rare example of divergent stereochemistry in an unusual amino acid residue that is present in two closely related classes of peptides.