RESUMO
Hepatitis C virus (HCV) infection represents a serious health-care problem. Previously we reported the identification of NA255 from our natural products library using a HCV sub-genomic replicon cell culture system. Herein, we report how the absolute stereochemistry of NA255 was determined and an enantioselective synthetic method for NA255 derivatives was developed. The structure-activity relationship of the NA255 derivatives and rat pharmacokinetic profiles of the representative compounds are disclosed.
Assuntos
Antivirais/síntese química , Citratos/química , Hepacivirus/crescimento & desenvolvimento , Fenilpropionatos/química , Animais , Antivirais/farmacocinética , Antivirais/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citratos/farmacocinética , Citratos/toxicidade , Meia-Vida , Hepacivirus/efeitos dos fármacos , Humanos , Fenilpropionatos/farmacocinética , Fenilpropionatos/toxicidade , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
The MAP kinase pathway is one of the most important pathways involved in cell proliferation and differentiation, and its components are promising targets for antitumor drugs. Design and synthesis of a novel MEK inhibitor, based on the 3D-structural information of the target enzyme, and then multidimensional optimization including metabolic stability, physicochemical properties and safety profiles were effectively performed and led to the identification of a clinical candidate for an orally available potent MEK inhibitor, CH4987655, possessing a unique 3-oxo-oxazinane ring structure at the 5-position of the benzamide core structure. CH4987655 exhibits slow dissociation from the MEK enzyme, remarkable in vivo antitumor efficacy both in mono- and combination therapy, desirable metabolic stability, and insignificant MEK inhibition in mouse brain, implying few CNS-related side effects in human. An excellent PK profile and clear target inhibition in PBMC were demonstrated in a healthy volunteer clinical study.
Assuntos
Antineoplásicos/química , Benzamidas/química , MAP Quinase Quinase Quinases/antagonistas & inibidores , Oxazinas/química , Inibidores de Proteínas Quinases/química , Administração Oral , Regulação Alostérica , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Benzamidas/administração & dosagem , Benzamidas/farmacologia , Humanos , Modelos Moleculares , Oxazinas/administração & dosagem , Oxazinas/farmacologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologiaRESUMO
Epolactaene, a neuritogenic compound in human neuroblastoma SH-SY5Y, induces apoptosis in a human leukemia B-cell line, BALL-1. The apoptosis-inducing activities of 34 epolactaene derivatives, including those of the newly synthesized alpha-alkyl-alpha,beta-epoxy-gamma-lactam derivative and cyclopropane derivatives, were also tested. The structure-activity relationships of the epolactaene derivatives as an inducer of apoptosis are described. The alpha-acyl-alpha,beta-epoxy-gamma-lactam moiety as well as the hydrophobicity derived from the long alkyl side chain are both important for activity. Compound 1e displayed the strongest activity among all the synthesized compounds with an IC50 value of 0.70 microM.