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Chemical Compound Review

Quinotaline     propan-2-yl (2S)-7-methoxy-2...

Synonyms: Talviraline, HBY-097, HBY097, CHEMBL430488, CHEBI:43101, ...
 
 
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Disease relevance of HBY 097

  • Second-generation non-nucleosidic reverse transcriptase inhibitor HBY097 and HIV-1 viral load [1].
  • The safety and antiviral activity of the second-generation nonnucleoside inhibitor HBY 097 was investigated in asymptomatic or mildly symptomatic human immunodeficiency virus (HIV)-1-infected patients in a randomized, double-blinded, dose-escalation study [2].
  • Both procedures were applied to the quantitation of HBY 097 and its metabolites in serum and urine of HIV positive patients who were enrolled in a clinical study of drug safety and pharmacokinetics [3].
 

High impact information on HBY 097

  • Although the RT alone and the RT/HBY 097 complex were crystallized in the presence of ATP, only the RT has an ATP coordinated with two Mn(2+) at the polymerase active site [4].
  • Crystal Structures of Clinically Relevant Lys103Asn/Tyr181Cys Double Mutant HIV-1 Reverse Transcriptase in Complexes with ATP and Non-nucleoside Inhibitor HBY 097 [4].
  • HBY 097 selects for unusual drug-resistance mutations in HIV-1 RT (e.g. Gly190Glu) when compared with other non-nucleoside RT inhibitors (NNRTIs), such as nevirapine, alpha-APA and TIBO [5].
  • Antiviral activity of the human immunodeficiency virus type 1-specific nonnucleoside reverse transcriptase inhibitor HBY 097 alone and in combination with zidovudine in a phase II study. HBY 097/2001 Study Group [2].
  • Given the exquisite potency of the combination of lamivudine and HBY 097 in suppressing viral replication, this combination should be further pursued in clinical trials examining treatment of HIV-1-infected persons [6].
 

Chemical compound and disease context of HBY 097

 

Biological context of HBY 097

  • Given the exquisite potency of a concomitant combination of 3TC and HBY 097 in suppressing virus replication, this drug combination should be further pursued in clinical trials in HIV-1-infected individuals [7].
  • Altered pharmacokinetics of indinavir by a novel nonnucleoside reverse transcriptase inhibitor (HBY-097): a pharmacokinetic evaluation in HIV-positive patients [8].
  • The resistant virus at study entry (IC50 = 160 nM) had a mutation at position 103 as well, combined with an AZT resistance mutation (K ==> R) at position 70, suggesting that nucleoside-resistance mutations may help increasing resistance to HBY 097 [9].
  • The lower quantitation limits were 25 ng ml-1 for HBY 097 and metabolites M2 and M3 in serum, and 0.5 microgram ml-1 for the metabolite M5 in urine measured as metabolite M3 after hydrolysis [3].
 

Anatomical context of HBY 097

 

Associations of HBY 097 with other chemical compounds

  • The HPLC procedure for the quantitation of HBY 097 and its metabolites M2 and M3 in human serum involved protein precipitation with acetonitrile followed by automated on-line trace enrichment [3].
 

Analytical, diagnostic and therapeutic context of HBY 097

  • The second generation Hoechst-Bayer non-nucleoside inhibitor, HBY 097 (S-4-isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3, 4-dihydroqui noxalin-2(1H)-thione), is an extremely potent inhibitor of HIV-1 reverse transcriptase (RT) and of HIV-1 infection in cell culture [5].
  • As a consequence of its outstanding properties, HBY 097 was selected for further development and is at present undergoing clinical trials [10].
  • Two HPLC methods were developed: one for the quantitation of HBY 097 reverse transcriptase inhibitor and its metabolites M2 and M3 in human serum, and one for the quantitation of metabolite M5 in urine [3].

References

  1. Second-generation non-nucleosidic reverse transcriptase inhibitor HBY097 and HIV-1 viral load. Rübsamen-Waigmann, H., Huguenel, E., Paessens, A., Kleim, J.P., Wainberg, M.A., Shah, A. Lancet (1997) [Pubmed]
  2. Antiviral activity of the human immunodeficiency virus type 1-specific nonnucleoside reverse transcriptase inhibitor HBY 097 alone and in combination with zidovudine in a phase II study. HBY 097/2001 Study Group. Kleim, J.P., Winters, M., Dunkler, A., Suarez, J.R., Riess, G., Winkler, I., Balzarini, J., Oette, D., Merigan, T.C. J. Infect. Dis. (1999) [Pubmed]
  3. Quantitative analysis of HBY 097 and its metabolites in human serum and urine by HPLC. Agarwal, V.K., Krol, G.J., Krone, V., Roberts, D. Journal of pharmaceutical and biomedical analysis. (1998) [Pubmed]
  4. Crystal Structures of Clinically Relevant Lys103Asn/Tyr181Cys Double Mutant HIV-1 Reverse Transcriptase in Complexes with ATP and Non-nucleoside Inhibitor HBY 097. Das, K., Sarafianos, S.G., Clark, A.D., Boyer, P.L., Hughes, S.H., Arnold, E. J. Mol. Biol. (2007) [Pubmed]
  5. Structures of Tyr188Leu mutant and wild-type HIV-1 reverse transcriptase complexed with the non-nucleoside inhibitor HBY 097: inhibitor flexibility is a useful design feature for reducing drug resistance. Hsiou, Y., Das, K., Ding, J., Clark, A.D., Kleim, J.P., Rösner, M., Winkler, I., Riess, G., Hughes, S.H., Arnold, E. J. Mol. Biol. (1998) [Pubmed]
  6. Zidovudine-resistant human immunodeficiency virus type 1 strains subcultured in the presence of both lamivudine and quinoxaline HBY 097 retain marked sensitivity to HBY 097 but not to lamivudine. Balzarini, J., Pelemans, H., Riess, G., Roesner, M., Winkler, I., De Clercq, E., Kleim, J.P. J. Infect. Dis. (1997) [Pubmed]
  7. Retention of marked sensitivity to (S)-4-isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3,4-di hydroquin oxaline-2(1H)-thione (HBY 097) by an azidothymidine (AZT)-resistant human immunodeficiency virus type 1 (HIV-1) strain subcultured in the combined presence of quinoxaline HBY 097 and 2',3'-dideoxy-3'-thiacytidine (lamivudine). Balzarini, J., Pelemans, H., Riess, G., Roesner, M., Winkler, I., De Clercq, E., Kleim, J.P. Biochem. Pharmacol. (1998) [Pubmed]
  8. Altered pharmacokinetics of indinavir by a novel nonnucleoside reverse transcriptase inhibitor (HBY-097): a pharmacokinetic evaluation in HIV-positive patients. Hayashi, S., Jayesekera, D., Jayewardene, A., Shah, A., Thevanayagam, L., Aweeka, F. Journal of clinical pharmacology. (1999) [Pubmed]
  9. Resistance mutations selected in vivo under therapy with anti-HIV drug HBY 097 differ from resistance pattern selected in vitro. Rübsamen-Waigmann, H., Huguenel, E., Shah, A., Paessens, A., Ruoff, H.J., von Briesen, H., Immelmann, A., Dietrich, U., Wainberg, M.A. Antiviral Res. (1999) [Pubmed]
  10. Preclinical evaluation of HBY 097, a new nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 replication. Kleim, J.P., Bender, R., Kirsch, R., Meichsner, C., Paessens, A., Rösner, M., Rübsamen-Waigmann, H., Kaiser, R., Wichers, M., Schneweis, K.E. Antimicrob. Agents Chemother. (1995) [Pubmed]
 
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