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Chemical Compound Review

CHEMBL2062137     (2S)-1-[(2S,4S)-2-hydroxy-4- [[(1R,2R)-2...

Synonyms: AKOS016007841, AC1L4BH9, AK105055, L-754394, L-754,394, ...
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Disease relevance of AIDS096249

  • Mechanism-based inactivation of human liver P450 3A4 by L-754,394, a Merck compound synthesized as a potential HIV protease inhibitor, was investigated using recombinant P450 3A4 [1].
  • L-754,394 is a potent and specific inhibitor of the HIV-1 encoded protease that is essential for the maturation of the infectious virus [2].

High impact information on AIDS096249

  • Mechanism-based inactivation of cytochrome P450 3A4 by L-754,394 [1].
  • The major and minor products formed during the inactivation of P450 3A4 were the monohydroxylated and the dihydrodiol metabolites of L-754,394, respectively [1].
  • Collectively, these results are taken to indicate that L-754,394 undergoes cytochrome P450-dependent oxidation of the fused furan ring system, leading to the formation of chemically-reactive intermediates [3].
  • In vitro studies on the metabolic activation of the furanopyridine L-754,394, a highly potent and selective mechanism-based inhibitor of cytochrome P450 3A4 [3].
  • When L-754,394 was incubated with monkey liver microsomes, the corresponding dihydrofurandiol was identified as a metabolite by liquid chromatography-tandem mass spectrometry [3].

Biological context of AIDS096249


Associations of AIDS096249 with other chemical compounds


Gene context of AIDS096249

  • To a lesser extent, L-754,394 also was an inactivator of CYP 2D6, for which the corresponding values for Kl, kinact and partition ratio were 32 microM, 0.18 min-1 and 40, respectively [6].
  • In the present studies, L-754,394 was demonstrated to undergo NADPH-dependent metabolic activation in hepatic microsomal preparations from rats, dogs, rhesus monkeys, and humans to electrophilic intermediates which became bound covalently to cellular proteins [3].

Analytical, diagnostic and therapeutic context of AIDS096249


  1. Mechanism-based inactivation of cytochrome P450 3A4 by L-754,394. Lightning, L.K., Jones, J.P., Friedberg, T., Pritchard, M.P., Shou, M., Rushmore, T.H., Trager, W.F. Biochemistry (2000) [Pubmed]
  2. Time- and dose-dependent pharmacokinetics of L-754,394, an HIV protease inhibitor, in rats, dogs and monkeys. Lin, J.H., Chiba, M., Chen, I.W., Vastag, K.J., Nishime, J.A., Dorsey, B.D., Michelson, S.R., McDaniel, S.L. J. Pharmacol. Exp. Ther. (1995) [Pubmed]
  3. In vitro studies on the metabolic activation of the furanopyridine L-754,394, a highly potent and selective mechanism-based inhibitor of cytochrome P450 3A4. Sahali-Sahly, Y., Balani, S.K., Lin, J.H., Baillie, T.A. Chem. Res. Toxicol. (1996) [Pubmed]
  4. Route-dependent nonlinear pharmacokinetics of a novel HIV protease inhibitor: involvement of enzyme inactivation. Lin, J.H., Chen, I.W., Chiba, M., Nishime, J.A., Deluna, F.A. Drug Metab. Dispos. (2000) [Pubmed]
  5. Comparative studies to determine the selective inhibitors for P-glycoprotein and cytochrome P4503A4. Achira, M., Suzuki, H., Ito, K., Sugiyama, Y. AAPS PharmSci (1999) [Pubmed]
  6. Potent and selective inactivation of human liver microsomal cytochrome P-450 isoforms by L-754,394, an investigational human immune deficiency virus protease inhibitor. Chiba, M., Nishime, J.A., Lin, J.H. J. Pharmacol. Exp. Ther. (1995) [Pubmed]
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