| Autor: |
Ding, C. Z., Batorsky, R., Bhide, R., Chao, H. J., Cho, Y., Chong, S., Gullo-Brown, J., Guo, P., Kim, S. H., Lee, F., Leftheris, K., Miller, A., Mitt, T., Patel, M., Penhallow, B. A., Ricca, C., Rose, W. C., Schmidt, R., Slusarchyk, W. A., Vite, G., Yan, N., Manne, V., Hunt, J. T. |
| Zdroj: |
Journal of Medicinal Chemistry; December 16, 1999, Vol. 42 Issue: 25 p5241-5253, 13p |
| Abstrakt: |
2,3,4,5-Tetrahydro-1-(imidazol-4-ylalkyl)-1,4-benzodiazepines were found to be potent inhibitors of farnesyltransferase (FT). A hydrophobic substituent at the 4-position of the benzodiazepine, linked via a hydrogen bond acceptor, was important to enzyme inhibitory activity. An aryl ring at position 7 or a hydrophobic group linked to the 8-position through an amide, carbamate, or urea linkage was also important for potent inhibition. 2,3,4,5-Tetrahydro-1-(1H-imidazol-4-ylmethyl)-7-(4-pyridinyl)-4-[2-(trifluoromethoxy)benzoyl]-1H-1,4-benzodiazepine (36), with an FT IC50 value of 24 nM, produced 85% phenotypic reversion of Ras transformed NIH 3T3 cells at 1.25 μM and had an EC50 of 160 nM for inhibition of anchorage-independent growth in soft agar of H-Ras transformed Rat-1 cells. Selected analogues demonstrated ip antitumor activity against an ip Rat-1 tumor in mice. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
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