Non-nucleoside RT inhibitors NNRTIs

Synthetic non-nucleoside RT inhibitor (NNRTI) in clinical use Synthetic nucleoside reverse transcriptase inhibitors (NRTIs) in clinical use metabolic conversion to the nucleoside triphosphate (NTP) (via the nucleoside monophosphate (NMP) and diphosphate (NDP)) gives DNA chain termination because of absence of 3 -hydroxyl (Note PMEA yields the phosphonate diphosphate ... 

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). 

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

Experience teaches us that combinations of active compounds offer the most promising perspective - for example, the combination of AZT with 3TC of BioChemPharma (Laval, Quebec, Canada). Currently (2003), there are seven approved entities of nucleoside analogs (NRTIs) and three approved non-nucleosides (NNRTIs) that inhibit reverse transcriptase (RT) by mimicking the structure of DNA building blocks and thus the copy process of RNA into DNA by reverse transcriptase. In addition, five HIV protease inhibitors and one viral fusion inhibitor have been approved. 

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 parallel, non-nucleoside reverse transcriptase inhibitors (NNRTIs) inhibit RT by a non-competitive binding to an allosteric site closely located to the catalytic site [18]. The short distances separating the allosteric and the binding sites suggest that NNRTIs alter the function of RT and directly disturb the interactions between the nucleotide natural substrates and the active site. 

The prototype compound of this family was the thymine derivative TSAO-T (Figure 2.18). TSAO derivatives were targeted at the HIV-l-encoded reverse transcriptase (RT) with which they interacted at a nonsubstrate binding site. Within the non-nucleoside reverse transcriptase inhibitors (NNRTIs), the TSAO nucleosides occupy a unique position in that they interfered at the interface between the P51 and P66 subunits of RT. A variety of 1,2,3-triazole TSAO derivatives (Figure 2.18) substituted at the 5-position of the triazole moiety were evaluated for their inhibitory effects against HIV-1- and HIV-2-induced cytopathicity in CEM and MT-4 cell cultures. The most active TSAO derivatives were those that contained either iV-ethyl (55) Af-cyclopropyl carbamoyl (56)... 

---