suggested that a potent tibo compound could partly supplement for the effects of the tyr-181c mutation by moving itself in the non-nucleoside inhibitor binding pocket (nnibp) of the mutant rt. in this context, r100943 has torsional freedom that enables the conformational alternations of the nnrti. this torsional freedom could be used by the itu derivate to bind to a mutated nnibp and thus compensating for the effects of a resistance mutation. nevertheless, the potency of r100943 against hiv-1 resistant mutants was not adequate for it to be considered as an effective drug candidate. additionally, the chemical stability of the imidoylthiourea part of the itu derivative was not favorable for an oral drug. development from itu to data figure 5 chemical substitutions of the dapy series were made to obtain the highly potent etravirine changes in the imidoylthiourea complexes led to the synthesis of a new class of compounds, diaryltriazine (data). in these compounds, the thiourea part of the itu compounds was replaced by a triazine ring. the data compounds were more potent than the itu compounds against common nnrti resistant mutant strains. r106168, a prototype data compound, was rather easy to synthesize. multiple substitutions were made at different positions on all of the three rings and on the linkers connecting the rings. in the pocket, most of the data derivatives conformed a horseshoe conformation. the two wings in r106168 (2,6-dichlorobenzyl and 4-cyanoanilino) occupied positions in the pocket similar to that of the two wings of the derivatives of itu. the central part of the data compounds, in which the triazine ring replaced the thiourea group of itu derivatives, is positioned between the side chains of l100 and v179. this removed a number of torsional degrees of freedom in the central part while keeping the flexibility between the triazine ring and the wings. chemical substitution or modification in the three-aromatic-ring backbone of the data compounds had substantial effect on the activity. r120393, a data analog, was designed with a chloroindole part in wing i to expand interactions with the side chain of conserved w229 of the polymerase primer grip loop. r120393 had similar effect as r106168 against most of the nnrti-resistant mutants. the cloroindole part interacted with the hydrophobic core of the pocket and influenced the binding mode of the r120393 so it went deeper into the pocket compared to the wing i position of other data analogs. crystal structures showed that the data compounds could bind the nnibp in different conformations. the capability to bind in multiple modes made the nnrtis stronger against drug-resistance mutations. variability between the inhibitors could be seen when the chemical composition, size of wing i and the two linker groups connecting the rings were altered. the potency of the nnrtis changed when the triazine nitrogen atoms were substituted with carbons. next generation nnrtis researchers used multi-disciplinary approach to design nnrtis with better resistance profile and an increased genetic barrier to the development of resistance. a new class of compounds, diarylpyrimide (dapy), were discovered with the replacement of the central triazine ring from the data compounds, with a pyrimidine. this new class was more effective against drug resistant hiv-1 strains than the corresponding data analogs. the replacement enabled substitutions to the ch-group at the 5-position of the central aromatic ring. one of the first dapy compounds, dapivirine (with r1= 2,4,6-trimethylanilino, r2 = r3 = h and y = nh) was found to be effective against drug-resistant hiv-1 strains. systematic chemical substitutions were made at the r1, r2, r3 and y positions to find new dapy derivatives. this led to the discovery of etravirine which has a bromine substitution at the 5-position (r3) of the pyrimidine ring (with r1 = 2,6-dimethyl-4-cyanoanilino, r2 = nh2 and y = o) (figure 5). etravirine was discovered by researchers at the jansen research foundation and tibotec and approved in 2008 by the fda. it is used in treatment-expirenced adult patients with hiv infection that is multidrug resistant in combination with other antiretroviral drugs. resistance when treating infection, whether bacterial or viral, there is always a risk of the infectious agent to develop drug resistance. the treatment of hiv infection is especially susceptible to drug resistance which is a serious clinical concern in the chemotherapeutic treatment of the infection. drug resistant hiv-strains emerge if the virus is able to replicate in the presence of the antiretroviral drugs. nnrti-resistant hiv-strains have the occurring mutations mainly in and around the nnibp affecting the nnrti binding directly by altering the size, shape and polarity on different areas of the pocket or by affecting, indirectly, the access to the pocket. those mutations are primarily noted in domains which span amino acids 98-108, 178-190 or 225-238 of the p66 subunit. the most frequent mutations observed in viruses isolated from patients who have been on a failing nnrti containing chemotherapy are lys-103n and tyr-181c. nnrti resistance has been linked to over 40 amino acid substitutions in vitro and in vivo. antiretroviral drugs are never used in monotherapy due to rapid resistance development. the highly active antiretroviral therapy (haart) was introduced in 1996. the treatment regimen combines three drugs from at least two different classes of antiretroviral drugs. the advance of etravirine over other nnrtis is that multiple mutations are required for the development of drug resistance. the drug has also shown activity against viruses with common nnrti resistance associated mutations and cross-resistance mutations. current status five drugs in the class of nnrtis have been approved by regulatory authorities. these are the first generation nnrtis nevirapine, delavirdine and efavirenz and the next generation nnrtis etravirine, and rilpivirine. several other nnrtis underwent clinical development but were discontinued due to unfavourable pharmacokinetic, efficacy and/or safety factors. currently there are four other nnrtis undergoing clinical development, idx899, rdea-428 and lersivirine (table 2). rilpivirine rilpivirine is a dapy compound like etravirine and was discovered when further optimization within this family of nnrtis was conducted. the resistance profile and the genetic barrier to the development of resistance is comparable to etravirine in vitro. the advantage of rilpivirine over etravirine is a better bioavailability and it is easier to formulate than etravirine. etravirine has required extensive chemical formulation work due to poor solubility and bioavailability. rilpivirine was approved by the fda for hiv therapy in may 2011 under the brand name edurant. edurant is approved for treatment-naive patients with a viral load of 100,000 copies/ml or less at therapy initiation. its recommended dosage is 25 mg orally once daily with a meal, in combination with other antiretrovirals. it is contraindicated for use with proton pump inhibitors due to the increased gastric ph causing decreased rilpivirine plasma concentrations, potentially resulting in loss of virologic response and possible resistance. a fixed-dose drug combining rilpivirine with emtricitabine and tenofovir disoproxil (tdf), was approved by the u.s. food and drug administration in august 2011 under the brand name complera. a newer fixed-dose drug also combining rilpivirine with emtricitabine and tenofovir alafenamide (taf) was approved in march 2016 under the brand name odefsey. rdea806 in 2007 a new family of triazole nnrtis was presented by researchers from the pharmaceutical company ardea biosciences. the selected candidate from the screening executed was rdea806 belonging to the family of triazoles. it has similar resistance profile against selected nnrti resistant hiv-1 strains to other next generation nnrtis. the candidate entered phase iib clinical trials in the end of 2009, but no further trial have been initiated. ardea was sold to astrazeneca in 2012. fosdevirine (idx899) fosdevirine (also known as idx899 and gsk-2248761) is another next generation nnrti developed by idenix pharmaceuticals and viiv healthcare. it belongs to the family of 3-phosphoindoles. in vitro studies have shown comparable resistance profile to that of the other next generation nnrtis. in november 2009 the candidate entered phase ii clinical trials, but the trial and all further development was halted when 5 of 35 subjects receiving fosdevirine experienced delayed-onset seizures. lersivirine (uk-453061) lersivirine belongs to the pyrazole family and is another next generation nnrti in clinical trials developed by the pharmaceutical company viiv healthcare. the resistance profile is similar to that of other next generation nnrtis. in the end of 2009 lersivirine was in phase iib. in february 2013, viiv healthcare announced a stop of the development program investigating lersivirine. table 2 represents the drug candidates that have been in clinical development drug candidate rdea806 fosdevirine (idx899) lersivirine (uk-453061) chemical structure phase of development iib ii iib