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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
Chemical Compound Review

Rescriptor     N-[2-[4-[3-(propan-2- ylamino)pyridin-2...

Synonyms: Delavirdine, CHEMBL593, SureCN34420, MET046, BHAP der, ...
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Disease relevance of U-90152S

  • Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis(heteroaryl)piperazine (BHAP) U-90152 explain resistance mutations for this nonnucleoside inhibitor [1].
  • Acute hypersensitivity with delavirdine [2].
  • Delavirdine boosted amprenavir trough levels more than 10-fold, and delavirdine trough levels remained i several fold above susceptible HIV strains [3].
  • CONCLUSIONS: Adding delavirdine to the combination regimen of patients in whom protease inhibitor therapy had failed often resulted in a rapid and remarkable decrease in viral load, sustained improvement in CD4+ lymphocyte counts and viral load, and clinical improvement with minimal toxicity [4].
  • Drug-resistant HIV-2 (EHO) variants containing the Ser102Leu and/or Glu219Asp mutations in their RT were selected after passaging the virus in MT-4 cells in the presence of increasing concentrations of delavirdine [5].

High impact information on U-90152S


Chemical compound and disease context of U-90152S


Biological context of U-90152S

  • The kinetics of inhibition of the Pro225His mutant RT by the NNRTIs (including BHAP U-90152) was not substantially different from that observed for the wild-type RT [15].
  • Plasma protein binding was linear for delavirdine in the escalating-dose and control groups; on average, the fraction unbound was about 2.3% and 2.0%, respectively [16].
  • Delavirdine could maximally inhibit 70% to 75% of predose ERMBT values, with an IC50 of about 0.9 mumol/L [16].
  • Consequently, the drug interaction profile and rationale for combining delavirdine with other antiretroviral agents is unique among the current NNRTI agents [17].
  • Delavirdine monotherapy has potent anti-HIV activity at 2 weeks, but its activity is time limited due to the rapid emergence of drug resistance [18].

Anatomical context of U-90152S

  • In a CD4+ T-cell line (H9) infected with HIV-1IIIB, the 50% effective concentrations for U-90152, AZT, and ddC were 6.0, 80.4, and 31.8 nM, respectively [19].
  • U-90152 had low cellular cytotoxicity, causing less than 8% reduction in peripheral blood lymphocyte viability at 100 microM [20].
  • CYP2D6 catalyzed desalkyl delavirdine formation was linear with time (up to 30 min) but when catalyzed by cDNA expressed CYP3A4 or human liver microsomes the reaction rate declined progressively with time [21].
  • Delavirdine desalkylation by microsomes pooled from several human livers was characterized by a KM of 6.8 +/- 0.8 microM and Vmax of 0 [22].
  • Delavirdine did not significantly cross the blood-brain barrier; however, its N-isopropylpyridinepiperazine metabolite arising from amide bond cleavage-was present in brain at levels 2- to 3-fold higher than in plasma [23].

Associations of U-90152S with other chemical compounds


Gene context of U-90152S

  • Delavirdine competitively inhibited recombinant CYP2D6 activity with a K(i) of 12.8+/-1.8 microM, similar to the observed K(M) for delavirdine desalkylation [27].
  • These results, along with previously reported experiments, indicate that delavirdine can partially inhibit CYP2C9, -2C19, -2D6, and -3A4, although the degree of inhibition in vivo would be subject to a variety of additional factors [27].
  • Delavirdine at concentrations up to 100 microM did not inhibit the activity of CYP1A2 or -2E1 [27].
  • Nevirapine did not inhibit hydroxylation of tolbutamide (CYP2C9) or S-mephenytoin (CYP2C19), but these CYP isoforms were importantly inhibited by delavirdine and efavirenz [28].
  • CONCLUSION: Delavirdine is a potent and reversible inhibitor of hepatic CYP3A; it is also a substrate for this CYP450 isoform [16].

Analytical, diagnostic and therapeutic context of U-90152S


  1. Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis(heteroaryl)piperazine (BHAP) U-90152 explain resistance mutations for this nonnucleoside inhibitor. Esnouf, R.M., Ren, J., Hopkins, A.L., Ross, C.K., Jones, E.Y., Stammers, D.K., Stuart, D.I. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  2. Acute hypersensitivity with delavirdine. Mills, G., Morgan, J., Hales, G., Smith, D. Antivir. Ther. (Lond.) (1999) [Pubmed]
  3. Long-term pharmacokinetics of amprenavir in combination with delavirdine in HIV-infected children. Engelhorn, C., Hoffmann, F., Kurowski, M., Stocker, H., Kruse, G., Notheis, G., Belohradsky, B.H., Wintergerst, U. AIDS (2004) [Pubmed]
  4. Clinical experience with adding delavirdine to combination therapy in patients in whom multiple antiretroviral treatment including protease inhibitors has failed. Bellman, P.C. AIDS (1998) [Pubmed]
  5. Activity of non-nucleoside reverse transcriptase inhibitors against HIV-2 and SIV. Witvrouw, M., Pannecouque, C., Van Laethem, K., Desmyter, J., De Clercq, E., Vandamme, A.M. AIDS (1999) [Pubmed]
  6. Continued lamivudine versus delavirdine in combination with indinavir and zidovudine or stavudine in lamivudine-experienced patients: results of Adult AIDS Clinical Trials Group protocol 370. Kuritzkes, D.R., Bassett, R.L., Johnson, V.A., Marschner, I.C., Eron, J.J., Sommadossi, J.P., Acosta, E.P., Murphy, R.L., Fife, K., Wood, K., Bell, D., Martinez, A., Pettinelli, C.B. AIDS (2000) [Pubmed]
  7. Amino acid substitutions at position 190 of human immunodeficiency virus type 1 reverse transcriptase increase susceptibility to delavirdine and impair virus replication. Huang, W., Gamarnik, A., Limoli, K., Petropoulos, C.J., Whitcomb, J.M. J. Virol. (2003) [Pubmed]
  8. Pharmacokinetic interaction between amprenavir and delavirdine: evidence of induced clearance by amprenavir. Tran, J.Q., Petersen, C., Garrett, M., Hee, B., Kerr, B.M. Clin. Pharmacol. Ther. (2002) [Pubmed]
  9. The P236L delavirdine-resistant human immunodeficiency virus type 1 mutant is replication defective and demonstrates alterations in both RNA 5'-end- and DNA 3'-end-directed RNase H activities. Gerondelis, P., Archer, R.H., Palaniappan, C., Reichman, R.C., Fay, P.J., Bambara, R.A., Demeter, L.M. J. Virol. (1999) [Pubmed]
  10. Antiviral activity of the dihydropyrone PNU-140690, a new nonpeptidic human immunodeficiency virus protease inhibitor. Poppe, S.M., Slade, D.E., Chong, K.T., Hinshaw, R.R., Pagano, P.J., Markowitz, M., Ho, D.D., Mo, H., Gorman, R.R., Dueweke, T.J., Thaisrivongs, S., Tarpley, W.G. Antimicrob. Agents Chemother. (1997) [Pubmed]
  11. Anti-human immunodeficiency virus type 1 activities of U-90152 and U-75875 in human brain cell cultures. Peterson, P.K., Gekker, G., Hu, S., Chao, C.C. Antimicrob. Agents Chemother. (1994) [Pubmed]
  12. Targeting delavirdine/atevirdine resistant HIV-1: identification of (alkylamino)piperidine-containing bis(heteroaryl)piperazines as broad spectrum HIV-1 reverse transcriptase inhibitors. Romero, D.L., Olmsted, R.A., Poel, T.J., Morge, R.A., Biles, C., Keiser, B.J., Kopta, L.A., Friis, J.M., Hosley, J.D., Stefanski, K.J., Wishka, D.G., Evans, D.B., Morris, J., Stehle, R.G., Sharma, S.K., Yagi, Y., Voorman, R.L., Adams, W.J., Tarpley, W.G., Thomas, R.C. J. Med. Chem. (1996) [Pubmed]
  13. Increased fidelity of drug-selected M184V mutated HIV-1 reverse transcriptase as the basis for the effectiveness of 3TC in HIV clinical trials. Wainberg, M.A. Leukemia (1997) [Pubmed]
  14. Effect of fluconazole on the steady-state pharmacokinetics of delavirdine in human immunodeficiency virus-positive patients. Borin, M.T., Cox, S.R., Herman, B.D., Carel, B.J., Anderson, R.D., Freimuth, W.W. Antimicrob. Agents Chemother. (1997) [Pubmed]
  15. Characteristics of the Pro225His mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase that appears under selective pressure of dose-escalating quinoxaline treatment of HIV-1. Pelemans, H., Esnouf, R., Dunkler, A., Parniak, M.A., Vandamme, A.M., Karlsson, A., De Clercq, E., Kleim, J.P., Balzarini, J. J. Virol. (1997) [Pubmed]
  16. Steady-state pharmacokinetics of delavirdine in HIV-positive patients: effect on erythromycin breath test. Cheng, C.L., Smith, D.E., Carver, P.L., Cox, S.R., Watkins, P.B., Blake, D.S., Kauffman, C.A., Meyer, K.M., Amidon, G.L., Stetson, P.L. Clin. Pharmacol. Ther. (1997) [Pubmed]
  17. Delavirdine: clinical pharmacokinetics and drug interactions. Tran, J.Q., Gerber, J.G., Kerr, B.M. Clinical pharmacokinetics. (2001) [Pubmed]
  18. ACTG 260: a randomized, phase I-II, dose-ranging trial of the anti-human immunodeficiency virus activity of delavirdine monotherapy. The AIDS Clinical Trials Group Protocol 260 Team. Para, M.F., Meehan, P., Holden-Wiltse, J., Fischl, M., Morse, G., Shafer, R., Demeter, L.M., Wood, K., Nevin, T., Virani-Ketter, N., Freimuth, W.W. Antimicrob. Agents Chemother. (1999) [Pubmed]
  19. Bisheteroarylpiperazine reverse transcriptase inhibitor in combination with 3'-azido-3'-deoxythymidine or 2',3'-dideoxycytidine synergistically inhibits human immunodeficiency virus type 1 replication in vitro. Chong, K.T., Pagano, P.J., Hinshaw, R.R. Antimicrob. Agents Chemother. (1994) [Pubmed]
  20. U-90152, a potent inhibitor of human immunodeficiency virus type 1 replication. Dueweke, T.J., Poppe, S.M., Romero, D.L., Swaney, S.M., So, A.G., Downey, K.M., Althaus, I.W., Reusser, F., Busso, M., Resnick, L. Antimicrob. Agents Chemother. (1993) [Pubmed]
  21. Microsomal metabolism of delavirdine: evidence for mechanism-based inactivation of human cytochrome P450 3A. Voorman, R.L., Maio, S.M., Payne, N.A., Zhao, Z., Koeplinger, K.A., Wang, X. J. Pharmacol. Exp. Ther. (1998) [Pubmed]
  22. Metabolism of delavirdine, a human immunodeficiency virus type-1 reverse transcriptase inhibitor, by microsomal cytochrome P450 in humans, rats, and other species: probable involvement of CYP2D6 and CYP3A. Voorman, R.L., Maio, S.M., Hauer, M.J., Sanders, P.E., Payne, N.A., Ackland, M.J. Drug Metab. Dispos. (1998) [Pubmed]
  23. Metabolism of the HIV-1 reverse transcriptase inhibitor delavirdine in mice. Chang, M., Sood, V.K., Wilson, G.J., Kloosterman, D.A., Sanders, P.E., Hauer, M.J., Zhang, W., Branstetter, D.G. Drug Metab. Dispos. (1997) [Pubmed]
  24. Pharmacokinetic study of the interaction between rifampin and delavirdine mesylate. Borin, M.T., Chambers, J.H., Carel, B.J., Gagnon, S., Freimuth, W.W. Clin. Pharmacol. Ther. (1997) [Pubmed]
  25. Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection. Fichtenbaum, C.J., Gerber, J.G. Clinical pharmacokinetics. (2002) [Pubmed]
  26. Pharmacokinetics of ritonavir and delavirdine in human immunodeficiency virus-infected patients. Shelton, M.J., Hewitt, R.G., Adams, J., Della-Coletta, A., Cox, S., Morse, G.D. Antimicrob. Agents Chemother. (2003) [Pubmed]
  27. Interaction of delavirdine with human liver microsomal cytochrome P450: inhibition of CYP2C9, CYP2C19, and CYP2D6. Voorman, R.L., Payne, N.A., Wienkers, L.C., Hauer, M.J., Sanders, P.E. Drug Metab. Dispos. (2001) [Pubmed]
  28. Inhibition of human cytochrome P450 isoforms by nonnucleoside reverse transcriptase inhibitors. von Moltke, L.L., Greenblatt, D.J., Granda, B.W., Giancarlo, G.M., Duan, S.X., Daily, J.P., Harmatz, J.S., Shader, R.I. Journal of clinical pharmacology. (2001) [Pubmed]
  29. Effect of delavirdine on plasma lipids and lipoproteins in patients receiving antiretroviral therapy. Roberts, A.D., Liappis, A.P., Chinn, C., Parenti, D.M., Muesing, R.A., Schuck, S.Z., Hsia, J., Simon, G.L. AIDS (2002) [Pubmed]
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