Non-nucleoside reverse transcriptase inhibitors NNRTIs

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... 

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. 

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). 

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. 

The second class of agents comprises non-competitive inhibitors of reverse transcriptase. These agents are also referred to as non-nucleoside reverse transcriptase inhibitors (NNRTIs). Unlike NRTIs, NNRTIs do not require phosphorylation to be activated and do not compete with nucleoside triphosphates. The NNRTIs bind to a site on the viral reverse transcriptase that is close to but separate from the NRTI receptor site. This binding ultimately results in blockade of RNA- and DNA-dependent DNA... 

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) delavirdine mesylate efavirenz nevirapine... 

NRTIs, which act as a substrate for RT, are not the only means of inhibiting reverse transcriptase. Like any enzyme, inhibitors can also bind allosteric positions away from the active site. An allosteric site on RT has been successfully targeted by drugs, and these drugs are called non-nucleoside reverse transcriptase inhibitors (NNRTIs). The three most frequently prescribed NNRTIs are shown in Figure A.46. 

In a review of the medical records of HIV-positive patients who had taken nevirapine, delavirdine, or both, the frequency of skin reactions was determined, as were the consequences of rechallenge with the same or the alternative agent (17). The overall incidence of rash attributed to the use of one of the non-nucleoside reverse transcriptase inhibitors (NNRTIs) was 37%. While rash due to delavirdine was more common (8/20 versus 25/69), the rash due to nevirapine was more severe and necessitated more frequent hospitalization. Rash recurred in six of eight patients who were rechallenged with the same agent and in seven of 10 who were switched to the alternative agent. The conclusion was drawn that there is little value in attempting to re-treat patients who have had skin reactions to NNRTIs, except possibly those with limited treatment options. 

There is no cure for AIDS. Treatment seeks to suppress symptoms (e.g., antibiotics for the infections) and slow viral reproduction. Mortality rates have decreased since 1995 because of the introduction of a treatment protocol called highly active antiretroviral therapy (HAART) that consists of combinations of drugs from the following categories (1) nucleoside reverse transcriptase inhibitors (NRTIs) (e.g., azidothymidine, also called zidovudine or AZT), (2) non-nucleoside reverse transcriptase inhibitors (NNRTIs) (e.g., efavirenz) and protease inhibitors (e.g., indinavir). Both NRTIs and NNRTIs inhibit vDNA synthesis catalyzed by reverse transcriptase. Protease inhibitors are a class of drugs that prevent the processing of viral protein that is required for the assembly of new virions. 

Scheme 19.24 Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Nevirapine 87 Deiavirdine 88 and Efavirenz 89. Circied portions of iead structures represent areas having probiematic metaboiism that were addressed during continued optimization to achieve the finai drug compounds. (With permission from Proudfoot.)...

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