RESUMEN
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.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/química , Compuestos Heterocíclicos/química , Inhibidores de Fosfodiesterasa/química , Pirazoles/química , Piridinas/química , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Humanos , Modelos Químicos , Modelos Moleculares , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/farmacología , Estructura Terciaria de Proteína , Pirazoles/síntesis química , Pirazoles/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
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.
Asunto(s)
Inhibidores de Fosfodiesterasa 4 , Inhibidores de Fosfodiesterasa/administración & dosificación , Inhibidores de Fosfodiesterasa/química , Quinolinas/administración & dosificación , Quinolinas/química , Administración Oral , Animales , Bovinos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Humanos , Masculino , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antiinflamatorios/química , Inhibidores de Fosfodiesterasa 4 , Inhibidores de Fosfodiesterasa/química , Quinolinas/química , Administración por Inhalación , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacocinética , Sitios de Unión , Dominio Catalítico , Cristalografía por Rayos X , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Humanos , Leucocitos Mononucleares/metabolismo , Lipopolisacáridos/farmacología , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/farmacocinética , Quinolinas/síntesis química , Quinolinas/farmacocinética , Ratas , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
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.
Asunto(s)
Aminas/síntesis química , Inhibidores de la Ciclooxigenasa 2/síntesis química , Éteres/síntesis química , Pirimidinas/síntesis química , Sulfonas/síntesis química , Aminas/farmacología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Química Farmacéutica/métodos , Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/farmacología , Modelos Animales de Enfermedad , Diseño de Fármacos , Éteres/farmacología , Humanos , Inflamación , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Enfermedades Neurodegenerativas/tratamiento farmacológico , Pirimidinas/farmacología , Ratas , Sulfonas/farmacologíaRESUMEN
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.