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

• 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 [6].
• 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) [7].

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

• HBY 097 was shown to be a highly potent inhibitor of HIV-1 induced cell killing and HIV-1 replication in a variety of human cell lines as well as in fresh human peripheral blood lymphocytes and macrophages [10].

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