HIV-1 non-nucleoside reverse transcriptase

Strategies for the design of HIV-1 non-nucleoside reverse transcriptase inhibitors 12JMC3595. 

Langmaim, P. Schirmer, D. Vath, T. Zilly, M. Klinker, H. High-performance liquid chromatographic method for the determination of HIV-1 non-nucleoside reverse transcriptase inhibitor efavirenz in plasma of patients during highly active antiretroviral therapy, J.Chromatogr.B, 2001, 755, 151-156. 

Hollanders, R.M.F. van Ewijk-Beneken Kohner, E.W.J. Burger, D.M. Wuis, E.W. Koopmans, P.P. Hekster, YA. Determination of nevirapine, an HIV-1 non-nucleoside reverse transcriptase inhibitor, in hmnan plasma by reversed-phase high-performance hquid chromatography, J.Chromatogr.B, 2000, 744, 65-71. [LOD 50 ng/mL LOQ 100 ng/mL]... 

Kauffman GS, Harris GD, Dorow RL, Stone BR, Parsons RL Jr, Pesti JA, Magnus NA, Fortunak JM, Confalone PN, Nugent WA (2000) An efficient chiral moderator prepared from inexpensive (+)-3-carene synthesis of the HIV-1 non-nucleoside reverse transcriptase inhibitor DPC 963. Org Lett 2 3119-3121... 

There are a few key enzymes for the proliferation of human immunodeficiency virus (HIV). Reverse transcriptase is one of them since HIV is a member of the DNA viruses. Efavirenz (1) is an orally active non-nucleoside reverse transcriptase inhibitor (NNRTI) and was discovered at Merck Research Laboratories [1] for treatment of HIV infections. Efavirenz was originally licensed to DuPont Merck Pharmaceuticals which was later acquired by Bristol-Myers Squibb.11 The typical adult dose is 600 mg once a day and 1 is one of three key ingredients of the once-a-day oral HIV drug, Atripla (Figure 1.1). 

Efavirenz (1) was chosen over compound 2 as a developmental candidate in 1993 based on its better antivirus activities, especially against resistant strains [1, 17]. Efavirenz is the first HIV non-nucleoside reverse transcriptase inhibitor (NNRTI) which was approved by the FDA on September 21, 1998. The original Medicinal Chemistry method to prepare Efavirenz is depicted in Scheme 1.14. 

The identification of the HIV-1-specific non-nucleoside reverse transcriptase inhibitors (NNRTIs) as a separate class of HIV inhibitors was heralded by the discovery of the tetrahydroimidazo[4,5,1 -// .][ 1,4]benzo-diazepin-2(l //)-onc and -thione (TIBO) derivatives (Fig. 7) [58,59] and 1 -(2-hydroxyethoxymethyl)-6-(phenylthio)thymine (HEPT) derivatives (Fig. 8) [60,61]. The first TIBO derivatives (R82150, R82913) were the first NNRTIs [58] postulated to act as inhibitors of HIV-1 RT [59], For the HEPT derivatives it became evident that they also interact specifically with HIV-1 RT after a number of derivatives (i.e., E-EPU, E-EBU, and E-EBU-dM) had been synthesized that were more active than HEPT itself [62,63]. Following HEPT and TIBO, several other compounds, i.e., nevirapine, pyridinone, and bis(heteroaryl)piperazine (BHAP), were... 

Nearly 40 million people are infected with the human immunodeficiency virus (HIV). Over half of those infected reside in sub-Saharan Africa. Worldwide during 2004, it is estimated that nearly 14,000 people a day were infected. Human immunodeficiency virus type 1 is the primary etiological source for the acquired immunodeficiency syndrome (AIDS). Fortunately, people infected with HIV are leading longer and more productive lives due to the availability of more effective therapies. Better medicines have evolved due to the efforts of scientists worldwide who find targets and compounds that inhibit the virus life-cycle. The current treatment for HIV infection is via a drug cocktail that usually includes a protease inhibitor (PI), a nucleoside reverse transcriptase inhibitor (NRTI), and a non-nucleoside reverse transcriptase inhibitor (NNRTI). 

Antibodies against the virus but also amantadine and derivatives, interfere with host cell penetration. There are nucleoside analogues such as aciclovir and ganciclovir, which interfere with DNA synthesis, especially of herpes viruses. Others like zidovudine and didanosine, inhibit reverse transcriptase of retroviruses. Recently a number of non-nucleoside reverse transcriptase inhibitors was developed for the treatment of HIV infections. Foscarnet, a pyrophosphate analogue, inhibits both reverse transcriptase and DNA synthesis. Protease inhibitors, also developed for the treatment of HIV infections, are active during the fifth step of virus replication. They prevent viral replication by inhibiting the activity of HIV-1 protease, an enzyme used by the viruses to cleave nascent proteins for final assembly of new vi-rons. 

Mechanism of Action A non-nucleoside reverse transcriptase inhibitor that binds directly to HlV-1 reverse transcriptase and blocks RNA- and DNA-dependent DNA polymerase activities. Therapeutic Effect Interrupts HIV replication, slowing the progression of HIV infection. 

Brennan TM, Taylor DL, Bridges CG, Leyda JP, Tyms AS. The inhibition of human immunodeficiency virus type 1 in vitro by a non-nucleoside reverse transcriptase inhibitor MKC-442 alone and in combination with other anti-HIV compounds. Antiviral Res 1995 26 173-187. 

Efavirenz (DMP 266) (1) is an effective non-nucleoside inhibitor of reverse transcriptase of the human immunodeficiency virus (HIV) recently registered by the US Food Drug Administration (FDA) for treatment of the acquired immunodeficiency syndrome (AIDS).1 2 3 Inhibition of HIV reverse transcriptase by nucleosides like azidothymidine (AZT) (2) is a proven therapy for delaying the progression to AIDS. However, the rapid viral mutation to resistant strains requires the development of new therapeutic agents. The recent development of both protease inhibitors and non-nucleoside reverse transcriptase inhibitors offers hope of effective treatment especially when coadministered. 

Abstract Non-nucleoside reverse transcriptase inhibitors, such as nevirapine, TIBO, HEPT, and efavirenz, are very specific to HIV-1 reverse transcriptase and have few side... 

Barreca et al screened for non-nucleoside reverse transcriptase inhibitors of HIV-1 by searching the Derwent World Drug Index (WDI) and the Chemicals Available for Purchase (CAP) databases with a Catalyst model generated by LigandScout. A Fit value cutoff of 3.0 and Lipinski filters, followed by docking, led to the selection of three compounds, two of which were commercially available. A search for available close analogues of all three compounds finally led to the purchase of six compounds, of which five were shown to be active. 

Efavirenz is a water-insoluble non-nucleoside reverse transcriptase inhibitor widely used as Sustiva tablets in the treatment of HIV infection, and is also available as an oral solution in which 30 mg/ml is dissolved in medium-chain triglycerides along with benzoic acid and strawberry/mint flavor. The daily dose of Efavirenz is 600 mg (20 ml) for adults and for pediatrics is 270-600 mg (9-20 ml) and these dosing regimens delivers the maximum amount of medium-chain triglycerides per unit dose of any currently marketed oral lipid-based formulation. Calcitrol is formulated in a fractionated triglyceride of palm seed oil in the 1 pg/ml Rocaltrol oral solution. The daily dose of calcitrol is 1 pg, which is only 1 ml of the oral solution. 

Clarke SM, Mulcahy EM, Tjia 1, Reynolds HE, Gibbons SE, Barry MG, Back Dl. The pharmacokinetics of methadone in HIV-positive patients receiving the non-nucleoside reverse transcriptase inhibitor efavirenz. Br J Chn Pharmacol 2001 51(3) 213-17. 

Nevirapine is a non-nucleoside reverse transcriptase inhibitor (1). Concerns about the adverse effects of nevirapine have delayed its implementation in preventing perinatal HIV. Decision analysis has been used to compare three strategies a single dose of nevirapine, a short course of zidovudine, and no intervention (2). The... 

In the laboratory of E.B. Pedersen, several 2-methylsulfanyl-1H-imidazoles were prepared and tested for their activity against HIV-1 These compounds can be regarded as novel non-nucleoside reverse transcriptase inhibitors. The required a-aminoketone hydrochloride building blocks were prepared using the Dakin-West reaction. L-Cyclohexylalanine was dissolved in excess pyridine and propionic anhydride and was kept at reflux overnight. The resulting a-propionylamino ethyl ketone was hydrolyzed with concentrated hydrochloric acid and the a-aminoketone hydrochloride was heated with one equivalent of potassium thiocyanate in water to afford 4-cyclohexylmethyl-5-ethyl-1,3-dihydroimidazole-2-thione. This material was then advanced to 4-cyclohexylmethyl-1-ethoxymethyl-5-ethyl-2-methylsulfanyl-IH-imidazole. 

Sakamoto, T., Cullen, M. D., Hartman, T. L., Watson, K. M., Buckheit, R. W, Pannecouque, C., De Clercq, E., Cushman, M. Synthesis and anti-HIV activity of new metabolically stable alke-nyldiarylmethane non-nucleoside reverse transcriptase inhibitors incorporating V-methoxy imidoyl halide and 1,2,4-oxadiazole systems. J. Med. Chem. 2007, 50(14), 3314-3321. 

The most prominent example of enantioselective organolithium additions to ketones is the development of the anti-AIDS drug efavirenz 23 (Scheme 3), a non-nucleoside reverse transcriptase inhibitor for a variety of HIV-1 mutant strains [88,89]. 

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