Disease relevance of Pyridinone

• L-697,661 is safe and well tolerated and has significant dose-related activity against HIV-1 [1].
• Pyridinone derivatives: specific human immunodeficiency virus type 1 reverse transcriptase inhibitors with antiviral activity [2].
• Plasma viremia as a sensitive indicator of the antiretroviral activity of L-697,661 [3].
• Possible toxicity associated with L-697,661 administration in a patient with AIDS [4].
• Michellamine B was active against a panel of biologically diverse laboratory and clinical strains of HIV-1, including the AZT-resistant strain G910-6 and the pyridinone-resistant strain A17; the compound also inhibited several strains of HIV-2 [5].

High impact information on Pyridinone

• Patients who received L-697,661 had rapid, dose-related decreases in plasma p24 antigen levels [1].
• Transient increases in CD4 counts were noted in the patients with fewer than 200 CD4 cells per cubic millimeter who received the two higher doses of L-697,661, but not in those who received the lowest dose or zidovudine [1].
• This change in susceptibility was more frequent among patients receiving the higher doses of L-697,661 and was associated with amino acid substitutions at positions 103 and 181 in the HIV-1 reverse transcriptase gene [1].
• We evaluated a pyridinone non-nucleoside reverse transcriptase inhibitor, L-697,661, in separate six-week double-blind trials in patients with HIV-1 infection whose CD4 counts ranged from 200 to 500 cells per cubic millimeter (68 patients) or less than 200 cells per cubic millimeter (67 patients) [1].
• It lost its sensitivity to the TSAO nucleosides but not to the other HIV-1-specific RT inhibitors (i.e., TIBO and pyridinone) [6].

Chemical compound and disease context of Pyridinone

• This quinazolinone binds to RT at a site that overlaps the binding site of other nonnucleoside inhibitors as evidenced by the ability of L-738,372 to displace bound radiolabeled L-696,229, a member of the pyridinone class of inhibitors of HIV-1 RT, from complexes of RT and primer-template [7].
• Combined therapy with zidovudine and L-697,661 in primary HIV infection [8].
• To test the concept that HIV reverse transcriptase could be effectively inhibited by "mixed site inhibitors", a series of seven conjugates containing both a nucleoside analogue component (AZT 1, ddC 2) and a nonnucleoside type inhibitor (HEPT analogue 12, pyridinone 27) were synthesized and evaluated for their ability to block HIV replication [9].

Biological context of Pyridinone

• The inhibition of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase by pyridinone compounds has been investigated using as templates synthetic RNA with sequences based on the HIV-1 genome sequence [10].
• These acids were examined for their ability to inhibit the rat passive cutaneous anaphylaxis; the pyridinone carboxylic acids 6 displayed a higher degree of iv and ip anaphylactic activities than their pyranone analogues 5 [11].
• The 3D-QSAR models derived will be used to guide the design of pyridinone derivatives active against mutant strains of reverse transcriptase [12].
• This methodology was applied to an expedient synthesis of (-)-barrenazine A and B. After N-functionalization and 1,4-reduction of the pyridinone system, the corresponding alpha-amino piperidinones readily undergo dimerization to give the hexahydrodipyridinopyrazine skeleton of the barrenazine alkaloids [13].
• Inhibition by nevirapine gave IC50 values of 0.15, 0.23 and 0.72 microM; by 9-Cl-TIBO of 0.20, 2.50 and 10.3 microM; by L-697,661 of 0.064, 0.28 and 0.60 microM; by ddGTP of 0.13, 0.14 and 0.02 microM; by PFA of 17.0, 48.0 and 15.0 microM for RT wt, RT (Arg-138) and RT (His-188), respectively [14].

Anatomical context of Pyridinone

• Chelation and determination of labile iron in primary hepatocytes by pyridinone fluorescent probes [15].

Associations of Pyridinone with other chemical compounds

• Further comparison of the 3'-CN-substituted benzoylpyridinone compound 18c, and the corresponding 3'-acrylonitrile-substituted analogue 30, to efavirenz, the reference molecule in anti-HIV therapy today, revealed that the pyridinone analogues displayed a superior inhibition profile in the in vitro cellular assay system [16].
• In our previous work we solved several X-ray structures of human alpha-thrombin in complexes with (1) novel bicyclic arginine mimetics attached to the glycylproline amide and pyridinone acetamide scaffold and (2) inhibitors with a novel aza scaffold and with charged or neutral P1 moieties [17].

Gene context of Pyridinone

• Phase 1 study of combination therapy with L-697,661 and zidovudine. The ACTG 184 Protocol Team [18].

Analytical, diagnostic and therapeutic context of Pyridinone

• Viral isolates were obtained from a subgroup of patients before and after treatment and were evaluated for in vitro sensitivity to L-697,661 [1].
• As one approach to define the mechanism of action of pyridinone inhibitors, we isolated resistant mutants of HIV-1 in cell culture [19].
• Whereas viral load decreases seen with zidovudine were sustained for the duration of treatment, plasma viral markers often returned to pretreatment levels despite ongoing L-697,661 treatment, with evidence of the emergence of drug-resistant virus [20].

References