Nonnucleoside reverse transcriptase inhibitors NNRTIs

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. 

Nonnucleoside reverse transcriptase inhibitor (NNRTI) A noncompetitive inhibitor of the viral reverse transcriptase enzyme that binds to the active site of the enzyme itself, rather than by terminating the enzymatic product. NNRTIs are only active against human immunodeficiency virus-1. 

The nonnucleoside reverse transcriptase inhibitors (NNRTIs), used in the treatment of AIDS, provide interesting examples of clinically relevant noncompetitive inhibitors. The causative agent of AIDS, HIV, belongs to a virus family that relies on an RNA-based genetic system. Replication of the vims requires reverse transcription of the viral genomic RNA into DNA, which is then incorporated into the genome of the infected host cell. Reverse transcription is catalyzed by a virally encoded nucleic acid polymerase, known as reverse transcriptase (RT). This enzyme is critical for viral replication inhibition of HIV RT is therefore an effective mechanism for abrogating infection in patients. 

Two papers described the optimization of LLE and physicochemical properties in a series of pyrazole HTV nonnucleoside reverse transcriptase inhibitors (NNRTIs) and the selection of lersivirine (6) as a development candidate [15,16]. The early lead (7) was relatively lipophilic (clogP = 4.3), rapidly metabolized in human liver microsomes and had an LLE of only 1.9 [pIC50 (HIV RT) - clogP] [15]. An optimization program targeting increased LLE in less lipophilic compounds of low MW (to... 

Nonnucleoside reverse transcriptase inhibitor (NNRTI) for combination with dual NRTIs (strength of recommendation in parentheses)... 

Pharmacology Delavirdine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Delavirdine binds directly to reverse transcriptase (RT) and blocks RNA-dependent and DNA-dependent DMA polymerase activities. 

The replicative cycle of HIV presents many opportunities for the targeting of antiviral agents. The drugs in clinical use are classified as nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NTRTIs), and protease inhibitors (PI). 

At the present time, there are at least 14 compounds that have been formally approved for the treatment of human immunodeficiency virus (HIV) infections. There are six nucleoside reverse transcriptase inhibitors (NRTIs) that, after their intracellular conversion to the 5 -triphosphate form, are able to interfere as competitive inhibitors of the normal substrates (dNTPs). These are zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), and abacavir (ABC). There are three nonnucleoside reverse transcriptase inhibitors (NNRTIs) — nevirapine, delavirdine, and efavirenz — that, as such, directly interact with the reverse transcriptase at a nonsubstrate binding, allosteric site. There are five HIV protease inhibitors (Pis saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir) that block the cleavage of precursor to mature HIV proteins, thus impairing the infectivity of the virus particles produced in the presence of these inhibitors. 

Nonnucleoside reverse transcriptase inhibitors NNRTIs are a distinct class of synthetic compounds that interfere with reverse transcriptase activity by binding next to the enzyme s active site, altering the configuration. NNRTIs are not phosphorylated and are only active against HIV-1, not HIV-2. 

Loksha, Y. M., El-Badawi, M. A., El-Barbary, A. A., Pedersen, E. B., Nielsen, C. Synthesis of 2-methylsulfanyl-1H-imidazoles as novel nonnucleoside reverse transcriptase inhibitors (NNRTIs). Arch. Pharm. (Weinheim, Ger.) 2003, 336, 175-180. 

Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) These bind to reverse transcriptase, disabling the reverse transcriptase. NNRTI medications are ... 

NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR (NNRTI) ANTIRETROVIRAL... 

Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI)-Based Regimens... 

ANTI-HIV AGENTS NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs)... 

In addition to NRTIs, the two other important classes of antiretroviral drugs available are the protease inhibitors and the nonnucleoside reverse transcriptase inhibitors (NNRTIs). Most authorities recommend initiation of antiretroviral therapy in treatment-naive patients with viral RNA loads above 10,(XX) copies/mL even if the CD4 cell count is normal. Preferred highly active antiretroviral therapy (HAART) combines one drug from the class of protease inhibitors with two NRTIs. Alternatively, one NNRTI may be combined with two NRTIs. 

Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) Antiretroviral Nucleoside Reverse Transcriptase Inhibitor (NRTI) Antiretroviral Protease Inhibitors Antiretroviral Fusion Inhibitors... 

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