| Autor: |
Dorsey, B. D., McDonough, C., McDaniel, S. L., Levin, R. B., Newton, C. L., Hoffman, J. M., Darke, P. L., Zugay-Murphy, J. A., Emini, E. A., Schleif, W. A., Olsen, D. B., Stahlhut, M. W., Rutkowski, C. A., Kuo, L. C., Lin, J. H., Chen, I-W., Michelson, S. R., Holloway, M. K., Huff, J. R., Vacca, J. P. |
| Zdroj: |
Journal of Medicinal Chemistry; September 7, 2000, Vol. 43 Issue: 18 p3386-3399, 14p |
| Abstrakt: |
Recent results from human clinical trials have established the critical role of HIV protease inhibitors in the treatment of acquired immune-deficiency syndrome (AIDS). However, the emergence of viral resistance, demanding treatment protocols, and adverse side effects have exposed the urgent need for a second generation of HIV protease inhibitors. The continued exploration of our hydroxylaminepentanamide (HAPA) transition-state isostere series of HIV protease inhibitors, which initially resulted in the identification of Crixivan (indinavir sulfate, MK-639, L-735,524), has now yielded MK-944a (L-756,423). This compound is potent, is selective, and competitively inhibits HIV-1 PR with a Ki value of 0.049 nM. It stops the spread of the HIVIIIb-infected MT4 lymphoid cells at 25.0−50.0 nM, even in the presence of α1 acid glycoprotein, human serum albumin, normal human serum, or fetal bovine serum. MK-944a has a longer half-life in several animal models (rats, dogs, and monkeys) than indinavir sulfate and is currently in advanced human clinical trials. |
| Databáze: |
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