Non-nucleoside reverse transcriptase

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... 

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

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)... 

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... 

A number of novel spiro heterocycles, including the triazepinethione 146 have been derived from 3-hydroxy-3-(2-oxocyclohexyl)indolin-2-one 145 by condensation with active methylene compounds <00SC1257>. A condensation process was also used to prepare tricyclic triazepinones related to the non-nucleoside reverse transcriptase inhibitor nevirapine <00JHC1539>. 

Nevirapine is a non-nucleoside reverse transcriptase inhibitor used to treat HIV-infected patients that causes mild to severe skin rash and even Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) in a substantial proportion (16%) of patients. Nevirapine also induces hepatotoxicity. These adverse clinical symptoms may also occur in non-HIV subjects taking the drug as postoperative prophylaxis [15]. 

Aubry, A.F., Sebastian, D., Hobson, T., Xu, J.Q., Rabel, S., Xie, M., and Gray, V., In-use testing of extemporaneously prepared suspension of second generation non-nucleoside reversed transcriptase inhibitors in support of Phase I clinical studies, /. Pharm. Biomed. Anal., 23,535,2000. 

Aubry, A.-E. et al.. Column selection and method development for the determination of the enantiomeric purity of investigational non-nucleoside reverse transcriptase inhibitors. Chirality, 13, 193, 2001. 

The development of antiretroviral therapy has been a major challenge since the discovery of the human inununodeficiency virus (HIV). Early successes with nucleoside and non-nucleoside reverse transcriptase (RT) inhibitors, as well as the development of protease inhibitors have facilitated, in recent years, a highly active antiretroviral therapy (HAART), where a combination of drugs is simultaneously administered. In spite of significant improvements in the morbidity and mortality of HIV-infected patients, the rapid appearance of resistant HIV-variants, as well as adverse effects and high cost of contemporary drugs necessitate the continuous development of independent classes of anti-HIV agents. ... 

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). 

Many of the drugs likely to be taken by patients with HIV have a strong potential to interact with the protease inhibitors. In particular, the non-nucleoside reverse transcriptase inhibitors are also metabolised by CYP450 and have been shown to interact with protease inhibitors. Delavirdine is an inhibitor of CYP3A4 but nevirapine and efavirenz are inducers of CYP3A4. The protease inhibitors also interact with each other, and these interactions are being explored for their potential therapeutic benefits. 

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. 

NRTI Nucleoside (or nucleotide) transcriptase inhibitor NNRTI Non-nucleoside reverse transcriptase inhibitor PI Protease inhibitor... 

Three non-nucleoside reverse transcriptase inhibitors (NNRTI) are currently used efavirenz (EFV), nevirapine (NVP) and delavirdine (DLV). The last NNRTI is not registered in Europe. 

Updated Guidelines for the Use of Rifabutin or Rifampin for the Treatment and Prevention of Thberculosis Among HIV-infected Patients Taking Protease Inhibitors or Non-nucleoside Reverse Transcriptase Inhibitors. Centers For Disease Control and Prevention MMWR 2000 49 185. 

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. 

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