RESUMEN
Three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling, comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA) of polyhydroxylated N-benzylbenzamide derivatives containing an adamantyl moiety were performed to understand the mechanism of action and structure-activity relationship of these compounds. Contour map analysis indicated that steric contributions of the adamantyl moiety and electrostatic contributions of the hydroxyl group at the 3-position are important in the activity. Activities of the training set and test sets predicted by CoMFA fit well with actual activities, demonstrating that CoMFA, along with the best calculated q(2) value, has the best predictive ability.
Asunto(s)
Benzamidas/química , Melaninas/antagonistas & inhibidores , Relación Estructura-Actividad Cuantitativa , Animales , Benzamidas/farmacología , Línea Celular Tumoral , Células Cultivadas , Melaninas/metabolismo , Melanocitos/efectos de los fármacos , Melanocitos/fisiología , Ratones , Estructura Secundaria de ProteínaRESUMEN
Interleukin-33 (IL-33) is an epithelial-derived cytokine that plays an important role in immune-mediated diseases such as asthma, atopic dermatitis, and rheumatoid arthritis. Although IL-33 is considered a potential target for the treatment of allergy-related diseases, no small molecule that inhibits IL-33 has been reported. Based on the structure-activity relationship and in vitro 2D NMR studies employing 15 N-labeled IL-33, we identified that the oxazolo[4,5-c]-quinolinone analog 7 c binds to the interface region of IL-33 and IL-33 receptor (ST2), an orphan receptor of the IL-1 receptor family. Compound 7 c effectively inhibited the production of IL-6 in human mast cells in a dose-dependent manner. Compound 7 c is the first low molecular weight IL-33 inhibitor and may be used as a prototype molecule for structural optimization and investigation of the IL-33/ST2 signaling pathway.
Asunto(s)
Diseño de Fármacos , Interleucina-33/antagonistas & inhibidores , Quinolonas/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Proteína 1 Similar al Receptor de Interleucina-1/antagonistas & inhibidores , Interleucina-6/antagonistas & inhibidores , Interleucina-6/biosíntesis , Mastocitos/efectos de los fármacos , Mastocitos/metabolismo , Estructura Molecular , Quinolonas/síntesis química , Quinolonas/químicaRESUMEN
A comparative molecular similarity indices analysis (CoMSIA) of a set of 42 3,4-dihydroquinazolines have been performed to find out the pharmacophore elements for T-type calcium channel blocking activity. The most potent compound, 33 (KYS05090) was used to align the molecules. As a result, we obtained 3D QSAR model which provided good predictivity for the training set (q(2)=0.642, r(2)=0.874) and the test set (r(pred)(2)=0.884). This model would guide the design of new chemical entities potentially having high potency.