Disease relevance of Coactinon

• OBJECTIVES: MKC-442 (6-benzyl-1-ethoxymethyl-5-isopropyluracil), a potent non-nucleoside reverse transcriptase inhibitor, is a promising candidate for the treatment of HIV-1 infection and is now undergoing clinical trials [1].
• Selective and synergistic inhibition of human immunodeficiency virus type 1 reverse transcriptase by a non-nucleoside inhibitor, MKC-442 [2].
• Since the compound has favorable pharmacokinetic and toxicity profiles in vivo, we have evaluated MKC-442 for its inhibitory effect on the replication of HIV-1 in various cell cultures, including human peripheral blood lymphocytes and monocyte-macrophages [3].

High impact information on Coactinon

• Three-drug combination of MKC-442, lamivudine and zidovudine in vitro: potential approach towards effective chemotherapy against HIV-1 [1].
• The IC50 value of MKC-442 for HIV-1 RT was 8 nM [2].
• These results suggest that MKC-442 is a unique inhibitor of HIV-1 RT, and combination therapy with MKC-442 and AZT could be advantageous in the treatment of acquired immune deficiency syndrome [2].
• MKC-442 did not inhibit HIV-1 RNase H, other RTs, or DNA polymerase alpha [2].
• Synthesis and evaluation of double-prodrugs against HIV. Conjugation of D4T with 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil (MKC-442, emivirine)-type reverse transcriptase inhibitors via the SATE prodrug approach [4].

Chemical compound and disease context of Coactinon

• Crystal structures of HIV-1 RT complexed with two very potent inhibitors, MKC-442 and TNK-651, at 2.55 angstroms resolution complement our previous analysis of the complex with the less effective inhibitor, HEPT [5].
• When the compounds were examined for their inhibitory effects on HIV-1 (HE strain) replication in MT-4 cells on day 4 after virus infection, the 50% effective concentrations (EC50) of MKC-442, nevirapine and loviride were 9.4, 98 and 21 nM, respectively [6].
• Notable synergistic inhibition of HIV-1 replication was observed when MKC-442 was combined with AZT and MDL-28,574 and moderate synergy with ddI [7].
• Synthesis of 6-arylvinyl analogues of the HIV drugs SJ-3366 and Emivirine [8].

Biological context of Coactinon

• Safety assessment, in vitro and in vivo, and pharmacokinetics of emivirine, a potent and selective nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 [9].
• Synthesis of these compounds was carried out starting from MKC-442 by a sequence of reactions (N3-protection, removal of N1-ethoxymethyl group, alkylation, and N3-deprotection) [10].
• These results indicate that the combination treatment with a relatively high dose of MKC-442 and a low dose of AZT may have potential to suppress the emergence of drug resistance during a long-term treatment in vivo and should be further pursued in HIV-1-infected patients [6].

Associations of Coactinon with other chemical compounds

• The ranking order of efficacy in cell-free RT inhibition assays was: HI-346 (IC50 = 0.4 microM) > HI-445 (IC50 = 0.5 microM) > trovirdine (IC50 = 0.8 microM) > MKC-442 (IC5 = 0.8 microM) = delavirdine (IC50 = 1.5 microM) > nevirapine (IC50 = 23 microM) [11].
• The activity of HI-236 against RT-MDR was superior to that of other anti-HIV agents tested, which are listed in the following order: HI-236 (IC50: 5 nM) > HI-240 (IC50: 6 nM) > trovirdine (IC50: 20 nM) > AZT (IC50: 150 nM) > MKC-442 (IC50: 300 nM) > delavirdine (IC50: 400 nM) > nevirapine (IC50: 5 microM) [12].

Gene context of Coactinon

• MKC-442 was also inhibitory to HIV-1 replication in peripheral blood lymphocytes and monocyte-macrophages as determined by the production of p24 antigens in the culture supernatant [3].
• The use of MKC-442 in a two- or three-drug combination regimen with other RT inhibitors, a proteinase inhibitor or an alpha-glucosidase 1 inhibitor should be considered for HIV-1-related chemotherapy [7].

Analytical, diagnostic and therapeutic context of Coactinon

• F(2)-NH-DABOs were shown to be highly active in both anti-RT and anti-HIV biological assays with IC(50) and EC(50) comparable with that of the reference compound MKC-442 [13].
• Emivirine (EMV) is a non-nucleoside reverse transcriptase inhibitor currently undergoing Phase III clinical trials in HIV-1-infected patients [14].

References