RESUMO
Toll-like receptor 4 (TLR4) induced proinflammatory signaling has been directly implicated in severe sepsis and represents an attractive therapeutic target. Herein, we report our investigations into the structure-activity relationship and preliminary drug metabolism/pharmacokinetics study of ß-amino alcohol derivatives that inhibit the TLR4 signaling pathway. Lead compounds were identified from in vitro cellular examination with micromolar potency for their inhibitory effects on TLR4 signaling and subsequently assessed for their ability to suppress the TLR4-induced inflammatory response in an ex vivo whole blood model. In addition, the toxicology, specificity, solubility, brain-blood barrier permeability, and drug metabolism of several compounds were evaluated. Although further optimizations are needed, our findings lay the groundwork for the future drug development of this class of small molecule agents for the treatment of severe sepsis.
Assuntos
Amino Álcoois/síntese química , Anti-Inflamatórios/síntese química , Receptor 4 Toll-Like/antagonistas & inibidores , Amino Álcoois/farmacocinética , Amino Álcoois/farmacologia , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Barreira Hematoencefálica/metabolismo , Linhagem Celular Tumoral , Humanos , Técnicas In Vitro , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Camundongos , Modelos Moleculares , Óxido Nítrico/biossíntese , Permeabilidade , Sepse/tratamento farmacológico , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Toll-like receptor 4 (TLR4), a membrane spanning receptor protein that functions in complex with its accessory protein MD-2, is an intriguing target for therapeutic development. Herein we report the identification of a series of novel TLR4 inhibitors and the development of a robust, enantioselective synthesis using an unprecedented Mannich-type reaction to functionalize a pyrazole ring. In silico and cellular assay results demonstrated that compound 1 and its analogues selectively block TLR4 activation in live cells. Animal model tests showed that 1 and its derivatives could potentiate morphine-induced analgesia in vivo, presumably by attenuating the opioid-induced TLR4 activation.