Future of nonnucleoside reverse transcriptase inhibitors

Sluis‐Cremer, Nicolas

doi:10.1073/pnas.1720975115

Cited by 17 publications

(16 citation statements)

References 13 publications

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“…Scheme 1 illustrates the synthesis of intermediate 2. Initially, the Heck reaction was performed by allowing the reaction between 4-bromo-2,6-dimethylaniline (4) and acrylamide (5) under inert conditions to achieve (2E)-3-(4-amino-3,5-dimethylphenyl)prop-2-enamide (6).…”

Section: Synthesis Of (2e)-3-(4-amino-35-dimethylphenyl) Prop-2-enenitrile Hydrochloride (Intermediate 2)mentioning

confidence: 99%

“…HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are an integral part of highly active antiretroviral therapy (HAART) due to its high tolerability and low toxicity. However, the rapid emergence of drug-resistant HIV-1 strains limited their clinical use [1][2][3][4][5][6][7]. Rilpivirine ((E)-4-((4-((4-(2-cyanovinyl)-2,6-dimethylphenyl)amino)pyrimidin-2-yl)amino)benzonitrile), is a successful second-generation NNRTI of diarylpyrimidine family (Fig.…”

Section: Introductionmentioning

confidence: 99%

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The development of an effective synthetic route of rilpivirine

et al. 2021

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Background Rilpivirine (RPV) was approved by the U.S. FDA (Food and Drug Administration) in 2011 to treat individuals infected with human immunodeficiency virus 1 (HIV-1). Significantly, rilpivirine is three fold more potent than etravirine. Once-daily, it is used with a low oral dose (25 mg/tablet), decreasing the drug administration and bringing a better choice to the patients. However, there are many shortcomings in the existing synthesis route of RPV, such as the high cost, prolonged reaction time and low yield (18.5%). Results This article describes our efforts to develop an efficient and practical microwave-promoted method to synthesize rilpivirine using less toxic organic reagents and low boiling solvents. The last step's reaction time decreased from 69 h to 90 min through this optimized synthetic procedure, and the overall yield improved from 18.5 to 21%. In addition, the yield of intermediate 3 increased from 52 to 62% compared to the original patent. Conclusion Overall, through a series of process optimization, we have developed a practical synthesis method of rilpivirine, which is easy to scale with higher yield and shorter reaction time.

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Section: Synthesis Of (2e)-3-(4-amino-35-dimethylphenyl) Prop-2-enenitrile Hydrochloride (Intermediate 2)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The development of an effective synthetic route of rilpivirine

et al. 2021

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“…Both features are of great interest for NNRTIs, as drugs are administrated in combination therapy during a lifelong treatment. Thus, the preclinical studies of the naphthyl phenyl ether ( 120 ) culminated almost a decade of drug development research and exposed the catechol series as promising next‐generation NNRTIs …”

Section: Drug Design Strategiesmentioning

confidence: 99%

Challenges and approaches in the discovery of human immunodeficiency virus type‐1 non‐nucleoside reverse transcriptase inhibitors

Battini

Bollini

2018

Medicinal Research Reviews

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The type I human immunodeficiency virus (HIV‐1) pandemic affecting over 37 million people worldwide continues, with 1.8 million people newly infected each year. Highly active antiretroviral therapy is efficient at reducing viral load and nearly one‐half of the infected population is on treatment. One of the most successful approaches for the treatment of HIV infections is the use of inhibitors for human immunodeficiency virus type‐1 reverse transcriptase (HIV‐1 RT). At present, there are six nonnucleoside reverse transcriptase inhibitors (NNRTIs) approved for clinical use: nevirapine (NVP), delavirdine (DLV), efavirenz (EFV), etravirine (ETV), rilpivirine (RPV), and elsulfavirine. In this review, we will cover the development of different classes of NNRTIs over the last two decades. We will give an overview of traditional medicinal chemistry strategies for structural modification as bioisosterism principles, scaffold hopping, substitute decoration, and molecular hybridization. Furthermore, computer‐aid design as virtual screening, de novo design and free‐energy perturbation will be described in details.

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“…HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are an integral part of highly active antiretroviral therapy (HAART) due to its high tolerability and low toxicity. However, the rapid emergence of drug-resistant HIV-1 strains limited their clinical use [1][2][3][4][5][6][7]. Rilpivirine ((E)-4-((4-((4-(2-cyanovinyl)-2,6dimethylphenyl)amino)pyrimidin-2-yl)amino)benzonitrile), is a successful second-generation NNRTI of diarylpyrimidine family (Fig.…”

Section: Introductionmentioning

confidence: 99%

The Development of An Effective Synthetic Route of Rilpivirine

Zhang

Yang

Zhou

et al. 2021

Preprint

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Background: Rilpivirine (RPV) is a potent and selective non-nucleoside reverse transcriptase inhibitor (NNRTI) of the diarylpyrimidine family with unique antiviral activity, low toxicity and high specificity. It is approved by the U.S. FDA (Food and Drug Administration) in 2011 to treat individuals infected with human immunodeficiency virus 1 (HIV-1). Significantly, rilpivirine is 3-fold more potent than etravirine. Once-daily, it is used with a low oral dose (25mg/tablet), decreasing the drug administration and bringing the better choice to the patients. However, there are many shortcomings in the existing synthesis route of RPV, such as the high cost, prolonged reaction time and low yield (18.5%).Results: This article describes our efforts to develop an efficient and practical microwave-promoted method to synthesize rilpivirine using less toxic organic reagents and low boiling solvents. The last step's reaction time decreased from 69 h to 90 min through this optimized synthetic procedure, and the overall yield improved from 18.5% to 21%. In addition, the yield of intermediate 3 increased from 52% to 62% compared to the original patent.Conclusion: Overall, through a series of process optimization, we have developed a practical synthesis method of rilpivirine, which is easy to scale with higher yield and shorter reaction time.

show abstract

Future of nonnucleoside reverse transcriptase inhibitors

Cited by 17 publications

References 13 publications

The development of an effective synthetic route of rilpivirine

The development of an effective synthetic route of rilpivirine

Challenges and approaches in the discovery of human immunodeficiency virus type‐1 non‐nucleoside reverse transcriptase inhibitors

The Development of An Effective Synthetic Route of Rilpivirine

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