Nucleoside reverse transcriptase

Hurwitz SJ, Schinazi RF (2002) Development of a pharmacodynamic model for HIV treatment with nucleoside reverse transcriptase and protease inhibitors. Antiviral Res 56 115-127 Hurwitz SJ, Tennant BC, Korba BE, Gerin JL, Schinazi RF (1998) Pharmacodynamics of (—)-beta-2, 3 -dideoxy-3 -thiacytidine in chronically virus-infected woodchucks compared to its pharmacodynamics in humans, Antimicrob Agents Chemother 42 2804-2809 Hurwitz SJ, Otto MJ, Schinazi RF (2005) Comparative pharmacokinetics of Racivir, (+/-)-beta-2, 3 -dideoxy-5-fluoro-3 -thiacytidine in rats, rabbits, dogs, monkeys and HIV-infected humans, Antivir Chem Chemother 16 117-127... 

The 2, 3 -dideoxynucleoside (ddN) analogues (Fig. 3) encompass a vast group of compounds that have been found active against HIV and HBV, although they have been primarily pursued for the treatment of HIV infections (AIDS). They are targeted at the HIV-associated reverse transcriptase (RT) and therefore also referred to as nucleoside reverse transcriptase inhibitors (NRTIs). They have to be distinguished from the nucleotide reverse transcriptase inhibitors (NtRTIs) such as adefovir (PMEA) and tenofovir (PMPA) (see above) which, like the NRTIs, act as chain... 

The first lead compounds for non-nucleoside reverse transcriptase (RT) inhibitors (NNRTl) were discovered about 15 years ago (Pauwels et al. 1990 Merluzzi et al. 1990 Goldman et al. 1991 De Clercq 1993 Riibsamen-Waigmann et al. 1997). Since then they have become an important ingredient of the dmg combination schemes that are currently used in the treatment of human immunodeficiency virus type 1 (HlV-1) infections. Starting from the HEPT and TIBO derivatives, numerous classes of compounds have been described as NNRTIs. Four compounds (nevirapine, delavirdine, efavirenz and etravirine) have so far been approved for clinical use and several others are the subject of clinical trials (Balzarini 2004 Stellbrink 2007). 

Herandez J, Amador L, Amantea M, Chao H, Hawley P, Paradise L (2000) Short-course monotherapy with AG1549, a novel non-nucleoside reverse transcriptase inhibitor (NNRTI), in antiretroviral naive patients. In 7th conference on retroviruses and opportunistic infections. San Francisco, CA, Abstract 669... 

There are currently six major antiretroviral drug families (Table 5). Nucleoside reverse transcriptase inhibitors (NRTI) are nucleoside analogs (discussed in more detail in chapter by De Clercq and Neyts, this volume) and were the first approved antiretroviral agents. They include drugs such as AZT, didanosine (ddl), stavudine (d4T), abacavir (ABC), and lamivudine (3TC), the latest used at doses of 300 mg daily as anti-HIV agent (lOOmg/day is the dosing approved for treatment of HBV... 

RT reverse transcriptase, NRTI nucleoside reverse transcriptase inhibitors, NNRTI Non-nucleoside reverse transcriptase inhibitors... 

Schweinsburg BC, Taylor MJ, Alhassoon OM, Gonzalez R, Brown GG, Ellis RJ, Letendre S, Videen JS, McCutchan JA, Patterson TL, Grant I (2005) Brain mitochondrial injury in human immunodeficiency virus-seropositive (HIV-I-) individuals taking nucleoside reverse transcriptase inhibitors. J Neurovirol ll(4) 356-364... 

Hannongbua S (2006) Structural Information and Drug-Enzyme Interaction of the Non-Nucleoside Reverse Transcriptase Inhibitors Based on Computational Chemistry Approaches. 4 55-84... 

Isoniazid Daily for 9 monthsc,d In human immunodeficiency virus (HlV)-infected patients, isoniazid may be administered concurrently with nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors, or non-nucleoside reverse transcriptase inhibitors (NNRTIs). A (II) A (II)... 

Treatment with two nucleoside reverse transcriptase inhibitors (NRTIs) and either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI) is the mainstay of treatment for HIV infection. 

NRTI, nucleoside reverse transcriptase inhibitor NNRTI, nonnucleoside reverse transcriptase inhibitor PI, protease inhibitor. 

AUC, area under the time-concentration curve ARV, antiretroviral AV, atrioventricular Cmax, maximum concentration CrCI, creatinine clearance ESRD, end-stage renal disease Cl, gastrointestinal HD, hemodialysis LFT, liver function test NRTI, nucleoside reverse transcriptase inhibitor UCT, uridine diphosphate-glucuronsyltransferase. 

TC, lamivudine ABC, abacavir APV, amprenavir AST, aspartate aminotransferase ALT, alanine aminotransferase ATV, atazanavir CBC, complete blood cell count D/C, discontinue ddl, didano-sine d4T, stavudine EFV, efavirenz FTC, emtricitabine P1BV, hepatitis B virus F1CV, hepatitis C vims HIV, human immunodeficiency virus IDV, indinavir IV, intravenous LFT, liver function tests LPV/r, lopinavir + ritonavir NNRTI, nonnucleoside reverse transcriptase inhibitor NRTI, nucleoside reverse transcriptase inhibitor NVP, nevirapine PI, protease inhibitor PT, prothrombin time T.bili, total bilirubin TDF, tenofovir disoproxiI fumarate TPV, tipranavir ULN, upper limit of normal ZDV, zidovudine. 

Nucleoside reverse transcriptase inhibitor (NRTI)/nucleotide reverse transcriptase inhibitor (NtRI) A modified version of a naturally-occurring nucleoside or nucleotide that prevents human immunodeficiency virus (HIV) replication by interfering with the function of the viral reverse transcriptase enzyme. The nucleoside/nucleotide analog causes early termination of the proviral DNA chain. For activity, an NRTI requires three phosphorylation steps once inside the cell, whereas an NtRI has a phosphate group attached and needs only two phosphorylation steps inside the cell for activity. 

Efavirenz , a Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI), and a Previous Structurally Related Development Candidate... 

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. 

VI. REVERSE TRANSCRIPTASE INHIBITORS INTERACTING WITH A NONSUBSTRATE BINDING SITE NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS... 

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... 

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