RESUMEN
The biphenyl amides (BPAs) are a series of p38alpha MAP kinase inhibitors. Compounds are able to bind to the kinase in either the DFG-in or DFG-out conformation, depending on substituents. X-ray, binding, kinetic and cellular data are shown, providing the most detailed comparison to date between potent compounds from the same chemical series that bind to different p38alpha conformations. DFG-out-binding compounds could be made more potent than DFG-in-binding compounds by increasing their size. Unexpectedly, compounds that bound to the DGF-out conformation showed diminished selectivity. The kinetics of binding to the isolated enzyme and the effects of compounds on cells were largely unaffected by the kinase conformation bound.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacología , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Amidas/sangre , Amidas/química , Aminoácidos/genética , Aminoácidos/metabolismo , Sitios de Unión , Compuestos de Bifenilo/sangre , Compuestos de Bifenilo/química , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Diseño de Fármacos , Lipopolisacáridos/farmacología , Conformación Molecular , Estructura Molecular , Naftalenos/farmacología , Pirazoles/farmacología , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Química Farmacéutica/métodos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/química , Inhibidores de Fosfodiesterasa 4 , Pirazoles/síntesis química , Pirazoles/farmacocinética , Piridinas/síntesis química , Piridinas/farmacocinética , Aminopiridinas/farmacología , Animales , Benzamidas/farmacología , Cristalografía por Rayos X/métodos , Ciclopropanos/farmacología , Diseño de Fármacos , Humanos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/metabolismo , Modelos Biológicos , Modelos Químicos , Pirrolidinonas/química , Ratas , Rolipram/farmacología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The biphenyl amides are a novel series of p38 MAP kinase inhibitors. Structure-activity relationships of the series against p38alpha are discussed with reference to the X-ray crystal structure of an example. The series was optimised rapidly to a compound showing oral activity in an in vivo disease model.