RESUMO
Following the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective phosphodiesterase 4B inhibitors, [Hamblin, J. N.; Angell, T.; Ballentine, S., et al. Bioorg. Med. Chem. Lett.2008, 18, 4237] the SAR of the 5-position was investigated further. A range of substituted heterocycles showed good potencies against PDE4. Optimisation using X-ray crystallography and computational modelling led to the discovery of 16, with sub-nM inhibition of LPS-induced TNF-α production from isolated human peripheral blood mononuclear cells.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Compostos Heterocíclicos/química , Inibidores de Fosfodiesterase/química , Pirazóis/química , Piridinas/química , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Humanos , Modelos Químicos , Modelos Moleculares , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacologia , Estrutura Terciária de Proteína , Pirazóis/síntese química , Pirazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Crystallography driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of quinoline-3-carboxamides as highly potent and selective inhibitors of phosphodiesterase 4B. This series has been optimized to GSK256066, a potent PDE4B inhibitor which also inhibits LPS induced production of TNF-alpha from isolated human peripheral blood mononuclear cells with a pIC(50) of 11.1. GSK256066 also has a suitable profile for inhaled dosing.
Assuntos
Anti-Inflamatórios/química , Inibidores da Fosfodiesterase 4 , Inibidores de Fosfodiesterase/química , Quinolinas/química , Administração por Inalação , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Humanos , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/farmacologia , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacocinética , Quinolinas/síntese química , Quinolinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
A novel series of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidine-based cyclooxygenase-2 (COX-2) inhibitors, which have a different arrangement of substituents compared to the more common 1,2-diarylheterocycle based molecules, have been discovered. For example, 2-(butyloxy)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (47), a member of the 2-pyrimidinyl ether series, has been shown to be a potent and selective inhibitor with a favourable pharmacokinetic profile, high brain penetration and good efficacy in rat models of hypersensitivity.
Assuntos
Aminas/síntese química , Inibidores de Ciclo-Oxigenase 2/síntese química , Éteres/síntese química , Pirimidinas/síntese química , Sulfonas/síntese química , Aminas/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Química Farmacêutica/métodos , Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Modelos Animais de Doenças , Desenho de Fármacos , Éteres/farmacologia , Humanos , Inflamação , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Doenças Neurodegenerativas/tratamento farmacológico , Pirimidinas/farmacologia , Ratos , Sulfonas/farmacologiaRESUMO
Crystallography-driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of a series of quinoline derivatives that were highly potent and selective inhibitors of PDE4 with a good pharmacokinetic profile in the rat. Quinolines 43 and 48 have potential as oral medicines for the treatment of COPD.
Assuntos
Inibidores da Fosfodiesterase 4 , Inibidores de Fosfodiesterase/administração & dosagem , Inibidores de Fosfodiesterase/química , Quinolinas/administração & dosagem , Quinolinas/química , Administração Oral , Animais , Bovinos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Humanos , Masculino , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Optimisation of a high-throughput screening hit resulted in the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective inhibitors of Phosphodiesterase 4 (PDE4). Herein, we describe early SAR studies around this novel template highlighting preferred substituents and rationalization of SAR through X-ray crystal structures of analogues bound to the PDE4 active site. Pyrazolopyridine 20a was found to be a potent and selective PDE4 inhibitor which also inhibits LPS induced TNF-alpha production from isolated human peripheral blood mononuclear cells and has an encouraging rat PK profile suitable for oral dosing.
