RESUMO
A series of amino acid prodrugs of NVR3-778, a potent anti-HBV candidate currently under phase II clinical trial, were designed and synthesized as new anti-HBV agents. Except for 1e, all of them displayed roughly comparable anti-HBV activity (IC50, 0.28-0.56 µM) to NVR3-778 (IC50, 0.26 µM). Compound 1a, a l-valine ester prodrug of NVR3-778, was found to show significantly improved water solubility (0.7 mg/mL, pH 2) as we expected, and lower cytotoxicity (CC50 > 10 µM) than NVR3-778 (CC50, 4.81 µM). Moreover, 1a also exhibited acceptable PK properties and comparable in vivo efficacy in HBV DNA hydrodynamic mouse model to that of NVR3-778, suggesting it may serve as a promising lead compound for further anti-HBV drug discovery.
Assuntos
Aminoácidos/química , Aminoácidos/metabolismo , Benzamidas/química , Vírus da Hepatite B/efeitos dos fármacos , Piperidinas/química , Pró-Fármacos , Antivirais , Desenho de Fármacos , Peptídeos/química , Peptídeos/metabolismo , Peptídeos/farmacologiaRESUMO
NVR3-778, one of the most advanced capsid assembly modulators (CAMs), is currently in phase II clinical trial for the treatment of HBV infection. In this study, we reported the first structure optimization of NVR3-778. Compound 2d was found to exhibit more potent anti-HBV activity (IC50: 0.25⯵M), lower cytotoxicity (CC50: 10.68⯵M) and higher selectivity index (SI: 40.72) than NVR3-778 (IC50: 0.33⯵M; CC50: 5.14⯵M; SI: 18.36) in vitro, and also display similar inhibitory effect on the assembly of HBV capsids as NVR3-778. Molecular docking further suggested that compound 2d might form a stronger interaction with core protein. Moreover, compound 2d also showed acceptable pharmacokinetic profiles. Currently compound 2d was selected as a new lead for further modifications, and studies to determine the in vivo anti-HBV studies of 2d will begin soon.
Assuntos
Antivirais/farmacologia , Benzamidas/farmacologia , Desenho de Fármacos , Vírus da Hepatite B/efeitos dos fármacos , Piperidinas/farmacologia , Antivirais/síntese química , Antivirais/química , Benzamidas/síntese química , Benzamidas/química , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-AtividadeRESUMO
We report herein the design and synthesis of a series of novel Sinefungin (SIN) derivatives, based on the structures of SIN and its analogue EPZ004777. Our results reveal that target compounds 1ad-af, 1ba-bb and 1bf-bh show better activity (IC50â¯=â¯4.56-20.16⯵M) than EPZ004777 (IC50â¯=â¯35.19⯵M). Surprisingly, SIN was founded to be not as active (IC50â¯>â¯50⯵M) as we and other research groups predicted. Interestingly, the intermediates 9a-b and 11b display potent anti-ZIKV potency (IC50â¯=â¯6.33-29.98⯵M), and compound 9a also exhibits acceptable cytotoxicity (CC50â¯>â¯200⯵M), suggesting their promising potential to be leads for further development.