| Autor: |
Burnouf, C., Auclair, E., Avenel, N., Bertin, B., Bigot, C., Calvet, A., Chan, K., Durand, C., Fasquelle, V., Feru, F., Gilbertsen, R., Jacobelli, H., Kebsi, A., Lallier, E., Maignel, J., Martin, B., Milano, S., Ouagued, M., Pascal, Y., Pruniaux, M.-P., Puaud, J., Rocher, M.-N., Terrasse, C., Wrigglesworth, R., Doherty, A. M. |
| Zdroj: |
Journal of Medicinal Chemistry; December 14, 2000, Vol. 43 Issue: 25 p4850-4867, 18p |
| Abstrakt: |
The synthesis, structure−activity relationships, and biological properties of a novel series of potent and selective phosphodiesterase type 4 (PDE4) inhibitors are described. These new aminodiazepinoindoles displayed in vitro PDE4 activity with submicromolar IC50 values and PDE4 selectivity vs PDE1, -3, and -5. Specifically, one compound (CI-1044, 10e) provided efficient in vitro inhibition of TNFα release from hPBMC and hWB with IC50 values of 0.34 and 0.84 μM, respectively. This compound was found to exhibit potent in vivo activity in antigen-induced eosinophil recruitment in Brown-Norway rats (ED50 = 3.2 mg/kg po) and in production of TNFα in Wistar rats (ED50 = 2.8 mg/kg po). No emetic side effects at therapeutic doses were observed in ferrets. |
| Databáze: |
Supplemental Index |
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