RESUMO
Inhibiting NLRP3 inflammasome activation is a prospective therapeutic strategy for uncontrolled inflammatory diseases. It is the first time that dronedarone, a multiply ion channel blocker, was identified as a NLRP3-inflammasome inhibitor with an IC50 value of 6.84 µM against IL-1ß release. A series of novel 5-amide benzofuran derivatives were designed and synthesized as NLRP3-inflammasome inhibitors. Compound 8c showed slightly increased activity (IC50 = 3.85 µM) against IL-1ß release. Notably, treatment with 8c could significantly inhibit NLRP3-mediated IL-1ß release and ameliorate peritoneal inflammation in a mouse model of sepsis. Collectively, 8c is a promising lead compound for further chemical development as a NLRP3 inhibitor with anti-inflammation effects.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Dronedarona/farmacologia , Descoberta de Drogas , Inflamassomos/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Relação Dose-Resposta a Droga , Dronedarona/síntese química , Dronedarona/química , Humanos , Inflamassomos/metabolismo , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/metabolismo , Estrutura Molecular , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Relação Estrutura-AtividadeRESUMO
A modification of the Nenitzescu reaction was used to obtain Dronedarone from quinonimine 20 and 1,3-diketone 14 (Râ¯=â¯CH2CH2CH2NBu2) in a two-stage process in almost 55% overall yield. Our results represent significant improvement over other state-of-the-art methods as no extra steps for the decoration of the benzofuran core are required.
Assuntos
Dronedarona/síntese química , Benzofuranos/química , Dronedarona/química , Cetonas/química , Estrutura Molecular , Quinonas/químicaRESUMO
Dronedarone is a new antiarrhythmic drug for the treatment of atrial fibrillation. This study investigated the complexation of dronedarone hydrochloride with ßcyclodextrin (ß-CD) and 2hydroxypropilßCD (HP-ß-CD) using three different techniques. The complexes in the solid state were characterized by DSC, TGA, PXRD, FT-IR, SEM and 1H NMR, demonstrating the formation of the inclusion complexes and exhibiting different properties from the pure drug. Its aqueous solubility increased about 4.0-fold upon complexation with ß-CD and HP-ß-CD. The dissolution rate of the drug was notably improved in all tested physiological pH values from 1.2 to 6.8 in the presence of both cyclodextrins. Furthermore, an in vitro cytotoxic assay revealed that the inclusion complexes could reduce the cytotoxic effects of the drug on 3T3 cells. The overall results suggest that the inclusion complexes with ß-CD and HP-ß-CD may be potentially useful in the preparation of novel pharmaceutical formulations containing dronedarone hydrochloride.