| Autor: |
Genin, M. J., Poel, T. J., May, P. D., Kopta, L. A., Yagi, Y., Olmsted, R. A., Friis, J. M., Voorman, R. L., Adams, W. J., Thomas, R. C., Romero, D. L. |
| Zdroj: |
Journal of Medicinal Chemistry; October 7, 1999, Vol. 42 Issue: 20 p4140-4149, 10p |
| Abstrakt: |
Development of resistance to currently approved HIV therapies has continued to fuel research efforts to improve the metabolic stability and spectrum of activity of the (alkylamino)piperidine-containing bis(heteroaryl)piperazine (AAP−BHAP) class of non-nucleoside reverse transcriptase inhibitors (NNRTIs). The synthesis of analogues in which the usual 3-alkylamino substituent on the pyridine ring is replaced by a 3-alkyl substituent led to compounds which retained activity against recombinant P236L and wild-type (WT) reverse transcriptase (RT), while inhibition of the Y181C mutant RT was reduced relative to the activity of the 3-alkylamino-substituted congeners. Testing of representative analogues in an in vitro liver microsome assay indicated that the alkyl substituent would not appreciably improve the metabolic stability of the AAP−BHAP template. In vivo pharmacokinetic evaluation of three compounds confirmed these results in that high systemic clearances were observed. Nevertheless, one compound (13), PNU-103657, possessed oral bioavailability in rats approaching that of the structurally related NNRTI drug delavirdine which is currently on the market for the treatment of HIV infection. |
| Databáze: |
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