Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The potential of a large variety of new compounds and new strategies for the treatment of virtually all major virus infections has been addressed. This includes, for the treatment of HIV infections, virus adsorption inhibitors (cosalane derivatives, cyanovirin-N), co-receptor antagonists (TAK-779, AMD3100), viral fusion inhibitors (pentafuside T-20, betulinic acid derivatives), viral uncoating inhibitors (azodicarbonamide), nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs: emtricitabine, amdoxovir, dOTC, d4TMP prodrugs, tenofovir disoproxil fumarate), non-nucleoside reverse transcriptase inhibitors (NNRTIs: thiocarboxanilide UC-781, capravirine, SJ-3366, DPC 083, TMC 125/R165335), integrase inhibitors (diketo acids), transcription inhibitors (temacrazine, flavopiridol), protease inhibitors (atazanavir, mozenavir, tipranavir); for the treatment of RSV and paramyxovirus infections, viral fusion inhibitors (R170591, VP-14637, NMS03); for the treatment of picornavirus infections, viral uncoating inhibitors (pleconaril); for the treatment of pesti- (hepaci-, flavi-) virus infections, RNA replicase inhibitors (VP-32947); for the treatment of herpesvirus (HSV, VZV, CMV) infections, DNA polymerase inhibitors (A-5021, L- and D-cyclohexenylguanine); for the treatment of VZV infections, bicyclic furopyrimidine analogues; for the treatment of CMV infections, fomivirsen; for the treatment of DNA virus infections at large (papilloma-, polyoma-, herpes-, adeno- and poxvirus infections), cidofovir; for the treatment of influenza, neuraminidase inhibitors (zanamivir, oseltamivir, RWJ-270201); for the treatment of HBV infections, adefovir dipivoxil; for the treatment of HBV and HCV infections, N-glycosylation inhibitors (N-nonyl-deoxynojirimycin); and, finally, IMP dehydrogenase inhibitors and S-adenosylhomocysteine hydrolase inhibitors, for the treatment of various virus infections, including hemorrhagic fever virus infections.
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PMID:Highlights in the development of new antiviral agents. 1237 77

(S)-5, 6-Difluoro-4-cyclopropylethynyl-4-trifluoromethyl-3, 4-dihydro- 2-(1H)-quinazolinone (DPC 963), a specific non-nucleoside inhibitor of human immunodeficiency virus-1 reverse transcriptase, is primarily metabolized in humans to the glucuronide conjugate of 8-OH DPC 963 (M8). Electrospray ionization-liquid chromatography/mass spectrometry analyses of urine from subjects dosed with DPC 963 also revealed the presence of other minor metabolites including glucuronide conjugate of 6-OH DPC 963 (M7). An oxidative defluorination pathway involving a putative p-benzoquinone imine capable of being reduced to the hydroquinone (M7) is postulated. The formation of the benzoquinone imine [detected as a glutathione (GSH) adduct, M5] was primarily carried out by CYP3A4, whereas M8 was formed mainly by the polymorphic CYP2B6. The kinetic studies with human liver microsomes showed that the apparent K(m) and V(max) values for the formation of M5 were 65.8 microM and 25.6 pmol/min/mg of protein, respectively. The formation of M8 showed K(m) and V(max) values of 15.1 microM and 22.9 pmol/min/mg of protein, respectively. The microsomal studies also revealed the occurrence of a possible oxirene intermediate that was trapped as GSH adducts M3 and M4. It was demonstrated, for the first time, that CYP3A4 was capable of directly oxidizing the triple bond of the cyclopropyl ethynyl group to an unstable oxirene. The apparent K(m) and V(max) values for the formation of an oxirene (detected as the GSH adduct M3) were 1.9 mM and 10.2 pmol/min/mg of protein, respectively. These results suggest that CYP2B6 has a higher affinity than CYP3A4 toward DPC 963. This consequently leads to greater levels of CYP2B6-catalyzed product, M8, than CYP3A4-mediated bioactivation of DPC 963 to benzoquinone imine or oxirene intermediates.
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PMID:Metabolism of (S)-5,6-difluoro-4-cyclopropylethynyl-4-trifluoromethyl-3, 4-dihydro-2(1H)-quinazolinone, a non-nucleoside reverse transcriptase inhibitor, in human liver microsomes. Metabolic activation and enzyme kinetics. 1248 61

The practical and highly diastereoselective syntheses of CF(3)-substituted dihydroquinazolinones via 1,4-additions of nucleophiles to chiral auxiliary substituted 2(3H)-quinazolinones is described. This methodology is applied to the syntheses of the NNRTIs (nonnucleoside reverse transcriptase inhibitors) DPC 961 (1) and DPC 083 (2), which are useful for the treatment of HIV (human immunodeficiency virus). The synthesis of DPC 961 (1) requires three steps, proceeds in >55% overall yield from the keto-aniline 9, and gives synthetic access to DPC 083 (2). In addition, the scope of the new diastereoselective 1,4-addition chemistry is investigated. The first preparation of DPC 961 (1) described in this paper is a derivatization fractional crystallization protocol.
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PMID:General scope of 1,4-diastereoselective additions to a 2(3H)-quinazolinone: practical preparation of HIV therapeutics. 1255 96

Despite the availability of 16 antiretroviral drugs approved for the treatment of HIV infection, current combination regimens present challenges. Newer antiretroviral drugs are needed to improve convenience, reduce toxicity and, of particular importance, to provide antiretroviral activity against viral strains resistant to the currently available antiretroviral agents. Candidate drugs with novel properties are in development in the two currently available drug classes: HIV reverse transcriptase inhibitors (nucleoside analogs, non-nucleoside analogs and nucleotide analogs) and HIV protease inhibitors (PI). Investigational nucleoside analog reverse transcriptase inhibitors (nRTI) include emtricitabine (FTC) and amdoxovir (DAPD), and investigational non-nucleoside reverse transcriptase inhibitors (NNRTI) include DPC 083 and TMC 125. New protease inhibitors under investigation include atazanavir (BMS-232 632), tipranavir, and TMC 114. In addition, newer agents with novel mechanisms of action such as HIV entry inhibitors (that inhibit the three steps of HIV entry: CD4 attachment, chemokine receptor binding and membrane fusion) and HIV integrase inhibitors are under investigation. Investigational entry inhibitors include PRO 542 (a CD4 attachment inhibitor), Schering C (a chemokine receptor inhibitor), enfuvirtide (T-20) and T-1249, inhibitors of membrane fusion. Investigational HIV integrase inhibitors include S-1360. Continued progress in the treatment of HIV disease will result from the development of new antiretroviral drugs.
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PMID:New antiretroviral drugs. 1266 50

The purpose of this research is to investigate the sublimation process of DPC 963, a second-generation nonnucleoside reverse transcriptase inhibitor for HIV-1 retrovirus, and to better understand the effect of sublimation during active pharmaceutical ingredient (API) manufacture and formulation development, especially the drying processes. Sublimation of DPC 963 at 150 degrees C and above was determined by thermogravimetric analysis-Fourier transform infrared (TGA-FTIR). The rates of sublimation at different temperatures were measured using isothermal TGA. Condensed material was collected and analyzed by differential scanning calorimetry (DSC), x-ray powder diffraction (XRPD), and infrared (IR) spectrometry. Benzoic acid was used as a reference standard to derive a linear logarithmic relationship between sublimation/evaporation rate and vapor pressure specific to the TGA system used in this study. Sublimation and evaporation of DPC 963 were found to follow apparent zero-order kinetics. Using the Eyring equation, the enthalpy and entropy of the sublimation and evaporation processes were obtained. The enthalpies of sublimation and evaporation were found to be 29 and 22 kcal/mol, respectively. The condensed material from the vapor phase was found to exist in 2 physical forms, amorphous and crystalline. Using benzoic acid as a reference standard, vapor pressure of DPC 963 at different temperatures was calculated using the linear logarithmic relationship obtained. DPC 963 undergoes sublimation at appreciable rates at 150 degrees C and above but this is not likely to pose a serious issue during the manufacturing process. Vapor pressure estimation using thermogravimetric analysis provided sufficient accuracy to be used as a fast, simple, and safe alternative to the traditional methods of vapor pressure determination.
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PMID:Sublimation characterization and vapor pressure estimation of an HIV nonnucleoside reverse transcriptase inhibitor using thermogravimetric analysis. 1291 5

DPC 963 is a non-nucleoside reverse transcriptase inhibitor with low aqueous solubility. The effect of DPC 963 drug substance particle size on the characteristics of granules manufactured by high-shear wet granulation was evaluated. The wet granulation process was used to manufacture a DPC 963 formulation with high drug loading. The formulation was manufactured using drug substance lots with different particle size distributions. Granulation particle size distribution, porosity, and compressibility were determined. A uniaxial compression test was also performed on moist compacts of the formulation prepared with different particle size distributions. Particle agglomeration behavior was affected by drug substance particle size. Granulation geometric mean diameter and fraction with particle size greater than 250 microm was inversely proportional to the drug substance particle size. Mercury intrusion porosimetry revealed higher pore volumes for the granules manufactured using the drug substance with the smaller particle size, suggesting lower tendency for granule densification than for that manufactured with the larger drug substance particle size. Granulation compressibility was also sensitive to changes in drug substance particle size. A decreased drug substance particle size led to increased granulation compressibility. Results from the uniaxial compression experiments suggested that the effect of particle size on granulation growth is the result of increased densification propensity, which in turn results from increased drug substance particle size.
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PMID:Effect of drug substance particle size on the characteristics of granulation manufactured in a high-shear mixer. 1472 98

There are now exactly 20 anti-HIV drugs licenced (approved) for clinical use, and > 30 anti-HIV compounds under (pre)clinical development. The licensed anti-HIV drugs fall into five categories: nucleoside reverse transcriptase inhibitors (NRTIs: zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir and emtricitabine); nucleotide reverse transcriptase inhibitors (NtRTIs: tenofovir disoproxil fumarate); non-nucleoside reverse transcriptase inhibitors (NNRTIs: nevirapine, delavirdine and efavirenz); protease inhibitors (PIs: saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, atazanavir and fosamprenavir); and fusion inhibitors (FIs: enfuvirtide). The compounds that are currently under clinical (Phase I, II or III) or preclinical investigation are either targeted at the same specific viral proteins as the licensed compounds (i.e., reverse transcriptase [NRTIs: PSI-5004, (-)-dOTC, DPC-817, elvucitabine, alovudine, MIV-210, amdoxovir, DOT; NNRTIs: thiocarboxanilide, UC-781, capravirine, dapivirine, etravirine, rilpivirine], protease [PIs: tipranavir, TMC-114]) or other specific viral proteins (i.e., gp120: cyanovirin N; attachment inhibitors: AIs, such as BMS-488043; integrase: L-870,812, PDPV-165; capsid proteins: PA-457, alpha-HCG); or cellular proteins (CD4 downmodulators: CADAs; CXCR4 antagonists: AMD-070, CS-3955; CCR5 antagonists: TAK-220, SCH-D, AK-602, UK-427857). Combination therapy is likely to remain the gold standard for the treatment of AIDS so as to maximise potency, minimise toxicity and diminish the risk for resistance development. Ideally, pill burden should be reduced to once-daily dosing so as to optimise the patient's compliance and reduce the treatment costs.
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PMID:Emerging anti-HIV drugs. 1593 66

Non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) have become an inherent ingredient of the drug combination schemes that are currently used in the treatment of human immunodeficiency virus type 1 (HIV-1) infections. Starting from the 1-[(2-hydroxyethoxy)methyl]-6-(phenylsulfanyl)thymine (HEPT) and 4,5,6,7-tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione (TIBO) derivatives, numerous classes of compounds have been described as NNRTIs. Only three compounds have so far been approved for clinical use: nevirapine, delavirdine, and efavirenz. NNRTIs are notorious for rapidly leading to virus-drug resistance development, primarily based on the emergence of the K103N and Y181C mutations in the HIV-1 RT. Newer NNRTIs, such as capravirine, dapivirine (TMC 125), and DPC 083, are resilient to these 'NNRTI' mutations, and, therefore, offer considerable promise as future anti-HIV-1 drugs. NNRTIs are targeted at a specific 'pocket' binding site within the HIV-1 RT, that is distinct from, but both spatially and functionally related to, the catalytic site, where the nucleoside RT inhibitors (NRTIs) and nucleotide RT inhibitors (NtRTIs) interact. NNRTIs have acquired a definitive position, as part of a combination regimen with NRTIs and NtRTIs, in the first-line treatment of HIV-1 infections.
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PMID:Non-nucleoside reverse transcriptase inhibitors (NNRTIs): past, present, and future. 1719 75


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