RESUMEN
Using cultured human mast cells (CHMC) the optimization of 2,4-diaminopyrimidine compounds leading to 22, R406 is described. Compound 22 is a potent upstream inhibitor of mast cell degranulation and its mechanism of action is via inhibition of Syk kinase. Compound 22 has significant activity in inhibiting both IgE- and IgG-mediated activation of Fc receptor (FcR) in mast cells and basophils, and in addition inhibits Syk kinase-dependent activity of FcR-mediated activation of monocytes, macrophages, neutrophils, and B cell receptor (BCR)-mediated activation of B lymphocytes. Overall, the biological activity of 22 suggests that it has potential for application as a novel therapeutic for the treatment of an array of autoimmune maladies and hematological malignancies.
Asunto(s)
Diseño de Fármacos , Inmunoglobulina E/inmunología , Inmunoglobulina G/inmunología , Pirimidinas/farmacología , Receptores Fc/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Here we report the optimization of small molecule inhibitors of human mast cell degranulation via anti-IgE-mediated tryptase release following cross-linking and activation of IgE-loaded FcεR1 receptors. The compounds are selective upstream inhibitors of FcεR1-dependent human mast cell degranulation and proved to be devoid of activity in downstream ionomycin mediated degranulation. Structure-activity relationship (SAR) leading to compound 26 is outlined.
Asunto(s)
Diseño de Fármacos , Inmunoglobulina E/inmunología , Mastocitos/efectos de los fármacos , Células Cultivadas , Humanos , Mastocitos/citología , Mastocitos/inmunología , Relación Estructura-ActividadRESUMEN
Two series of 4-arylpiperidinyl amide and N-arylpiperdin-3-yl-cyclopropane carboxamide derivatives exhibiting diverse functionality at rat MT(1) and MT(2) receptors are reported. Compounds 11f and 18b (MT(1)/MT(2) agonist) have human microsomal intrinsic clearance comparable to ramelteon.
Asunto(s)
Amidas/química , Ciclopropanos/síntesis química , Piperidinas/síntesis química , Receptor de Melatonina MT1/agonistas , Receptor de Melatonina MT2/agonistas , Amidas/síntesis química , Amidas/farmacología , Animales , Ciclopropanos/química , Ciclopropanos/farmacología , Diseño de Fármacos , Humanos , Ligandos , Microsomas/metabolismo , Piperidinas/química , Piperidinas/farmacología , Ratas , Receptor de Melatonina MT1/metabolismo , Receptor de Melatonina MT2/metabolismo , Relación Estructura-ActividadRESUMEN
Gangliosides have been described as modulators of growth factor receptor activity and subsequent cellular function. Due to the lower-pH environment found in tumor cells, ganglosides are thought to be formed (at least to some extent) into their lactone forms. The aim of the study was to analyze the mode of action of the lactone of the ganglioside GM3 on epidermal growth factor (EGF) signaling in human ovarial epidermoid carcinoma A431 cells and cell growth in human oral epidermoid carcinoma KB cells by applying the GM3 lactone analog HK1-ceramide 2, which is stable under hydrolytic conditions. Specific inhibition of EGF-dependent receptor tyrosine phosphorylation was observed by HK1-ceramide 2 at 25 microM, whereas GM3 showed a comparable inhibition at eightfold higher concentrations. In cells exposed to low pH, where GM3 is thought to form its lactone to a higher extent, addition of GM3 showed no further inhibitory effect on EGF-dependent receptor phosphorylation. Similarly to GM3, HK1-ceramide 2 does not affect binding of (125)I-EGF to the cell surface receptor. EGF-dependent growth of KB cells was also found to be inhibited by HK1-ceramide 2 at much lower concentrations compared to GM3. In conclusion, our results indicate that the GM3 lactone analog HK1-ceramide 2 is a specific inhibitor of EGF receptor function and is more potent in reducing EGF-dependent tyrosine phosphorylation of the receptor in A431 cells and in inhibiting EGF-dependent growth of KB cells compared to GM3.