RESUMO
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.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Amidas/sangue , Amidas/química , Aminoácidos/genética , Aminoácidos/metabolismo , Sítios de Ligação , Compostos de Bifenilo/sangue , Compostos de Bifenilo/química , Técnicas de Química Combinatória , Cristalografia por Raios X , Desenho de Fármacos , Lipopolissacarídeos/farmacologia , Conformação Molecular , Estrutura Molecular , Naftalenos/farmacologia , Pirazóis/farmacologia , 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.
Assuntos
Química Farmacêutica/métodos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Inibidores da Fosfodiesterase 4 , Pirazóis/síntese química , Pirazóis/farmacocinética , Piridinas/síntese química , Piridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Benzamidas/farmacologia , Cristalografia por Raios X/métodos , Ciclopropanos/farmacologia , Desenho de Fármacos , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Modelos Biológicos , Modelos Químicos , Pirrolidinonas/química , Ratos , Rolipram/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
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.