Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: A review of the last 20 years (1989–2009)

Béthune, Marie‐Pierre de

doi:10.1016/j.antiviral.2009.09.008

Cited by 354 publications

(289 citation statements)

References 173 publications

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“…These include nucleoside 2 and non-nucleoside 3 inhibitors of reverse transcriptase (RT), inhibtors of HIV protease, 4 strand transfer inhibitors of integrase (IN), 5,6 chemokine receptor 5 (CCR5) antagonists, and HIV entry inhibitors, 7 all of which have marketed drugs available to patients. Additionally, a number of investigational mechanisms of action have been identified, 8 including noncatalytic site integrase inhibitors (NCINIs), first disclosed in 2007.…”

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confidence: 99%

Minimizing the Contribution of Enterohepatic Recirculation to Clearance in Rat for the NCINI Class of Inhibitors of HIV

Fader

Carson

Morin

et al. 2014

ACS Med. Chem. Lett.

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A scaffold replacement approach was used to identifying the pyridine series of noncatalytic site integrase inhibitors. These molecules bind with higher affinity to a tetrameric form compared to a dimeric form of integrase. Optimization of the C6 and C4 positions revealed that viruses harboring T124 or A124 amino acid substitutions are highly susceptible to these inhibitors, but viruses having the N124 amino acid substitution are about 100-fold less susceptible. Compound 20 had EC 50 values <10 nM against viruses having T124 or A124 substitutions in IN and >800 nM in viruses having N124 substitions. Compound 20 had an excellent in vitro ADME profile and demonstrated reduced contribution of biliary excretion to in vivo clearance compared to BI 224436, the lead compound from the quinoline series of NCINIs. KEYWORDS: NCINI, enterohepatic recirculation, biliary excretion, integrase tetramer S ince the discovery of HIV in 1983, it is estimated that about 36 million people have died from AIDS worldwide.1 There has been a continuous search for antiretroviral (ARV) agents to combat HIV, which has led to the discovery of a number of mechanistic classes of replication inhibitors. 9 Recent work has shown that this class of inhibitor binds to an allosteric pocket on the catalytic core domain (CCD) of IN, shifting the oligomerization equilibrium of IN toward the tetrameric state.10−12 This aberrant multimerization negatively impacts viral maturation, which leads to the NCINI antiviral effect. 13,14Recently we disclosed our discovery of the NCINIs, culminating in the identification of BI 224436, the first compound from this mechanistic class to advance into clinical trials. 15 Compound 1 exemplifies the structural features of the prototypical quinolone series. The methyl substitution at C2 orients the C3 acetic acid group, favoring the bioactive form, and C4 bears an aromatic core. We demonstrated the importance of the C3 and C4 substituents in binding to IN CCD, which included hydrogen bonding interactions between the carboxylic acid and the backbone amide protons of residues E170 and H171 of IN. It was found that this interaction was critical to antiviral potency and that there was no tolerated isosteric replacement for the acid. The presence of a carboxylic acid can complicate the development of a lead series into a marketed drug for a number of reasons. 16,17 In the case of BI 224436, we found that the extremely low in vivo clearance of this molecule in rat is attributable to enterohepatic recirculation involving excretion of parent and the corresponding acyl glucuronide into the bile, reentry into the gastrointestinal tract, and reabsorption of parent back into the hepatic portal system. This phenomenon was common to all members of the NCINI class that were evaluated in rat pharmacokinetic experiments. The potential variability of the contribution of enterohepatic recirculation to in vivo clearance across species introduces uncertainty in allometric scaling and prediction of human PK parameters, which can compli...

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confidence: 99%

Minimizing the Contribution of Enterohepatic Recirculation to Clearance in Rat for the NCINI Class of Inhibitors of HIV

Fader

Carson

Morin

et al. 2014

ACS Med. Chem. Lett.

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“…In fact, studies are underway to develop a new once-daily fixed-dose antiretroviral regimen containing Emtricitabine, Tenofovir disoproxil fumarate and Rilpivirine hydrochloride (de Béthune, 2010). Rilpivirine has an in vitro resistance profile comparable to that of ETR (Azijn, 2010), and results from week 96 of a Phase IIB trial (TMC278-C204) in naïve patients have demonstrated a potent and sustained efficacy similar to that of EFV, while it seems to produce fewer adverse events.…”

Section: Rilpivirine (Tmc278)mentioning

confidence: 99%

Future Perspectives in NNRTI-Based Therapy: Bases for Understanding Their Toxicity

Blas‐García¹,

Apostolova²,

Esplugues³

2011

Recent Translational Research in HIV/AIDS

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“…4,5 NNRTIs that interact noncompetitively with an allosteric binding pocket in the vicinity of the reverse transcriptase's (RT's) polymerase active site are an important component of first-line regimens. 6 Although there are five-FDA approved NNRTIs for clinical use (Figure 1), alternatives are still needed due to the tendency of HIV-1 to rapidly mutate. Prolonged HAART treatment leads to the emergence of drug-resistant viral mutants.…”

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confidence: 99%

Discovery of Phenylaminopyridine Derivatives as Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors

Kim¹,

Lee²,

Park³

et al. 2012

ACS Med. Chem. Lett.

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ABSTRACT:We identified a novel class of aryl-substituted triazine compounds as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) during a high-throughput screening campaign that evaluated more than 200000 compounds for antihuman immunodeficiency virus (HIV) activity using a cell-based full replication assay. Herein, we disclose the optimization of the antiviral activity in a cell-based assay system leading to the discovery of compound 27, which possessed excellent potency against wild-type HIV-1 (EC 50 = 0.2 nM) as well as viruses bearing Y181C and K103N resistance mutations in the reverse transcriptase gene. The X-ray crystal structure of compound 27 complexed with wild-type reverse transcriptase confirmed the mode of action of this novel class of NNRTIs. Introduction of a chloro functional group in the pyrazole moiety dramatically improved hERG and CYP inhibition profiles, yielding highly promising leads for further development.

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Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: A review of the last 20 years (1989–2009)

Cited by 354 publications

References 173 publications

Minimizing the Contribution of Enterohepatic Recirculation to Clearance in Rat for the NCINI Class of Inhibitors of HIV

Minimizing the Contribution of Enterohepatic Recirculation to Clearance in Rat for the NCINI Class of Inhibitors of HIV

Future Perspectives in NNRTI-Based Therapy: Bases for Understanding Their Toxicity

Discovery of Phenylaminopyridine Derivatives as Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors

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