7‐Step Flow Synthesis of the HIV Integrase Inhibitor Dolutegravir

Ziegler, Robert; Desai, Bimbisar; Jee, Jo‐Ann; Gupton, B. Frank; Roper, Thomas D.; Jamison, Timothy F.

doi:10.1002/anie.201802256

Cited by 85 publications

(60 citation statements)

References 56 publications

(16 reference statements)

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“…Dual therapies have begun to replace other cARTs as a maintenance strategy for improving adherence and safety. A number of dual therapies that combine ETR or RPV with an INSTI are [42,[66][67][68]. Important single bonds with broad rotational flexibility are shown in red or with partial flexibility in blue.…”

Section: Dapy/insti Dual Therapiesmentioning

confidence: 99%

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Non-Nucleoside Reverse Transcriptase Inhibitors Join Forces with Integrase Inhibitors to Combat HIV

Himmel¹,

Arnold

2020

Pharmaceuticals

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In the treatment of acquired immune deficiency syndrome (AIDS), the diarylpyrimidine (DAPY) analogs etravirine (ETR) and rilpivirine (RPV) have been widely effective against human immunodeficiency virus (HIV) variants that are resistant to other non-nucleoside reverse transcriptase inhibitors (NNRTIs). With non-inferior or improved efficacy, better safety profiles, and lower doses or pill burdens than other NNRTIs in the clinic, combination therapies including either of these two drugs have led to higher adherence than other NNRTI-containing treatments. In a separate development, HIV integrase strand transfer inhibitors (INSTIs) have shown efficacy in treating AIDS, including raltegravir (RAL), elvitegravir (EVG), cabotegravir (CAB), bictegravir (BIC), and dolutegravir (DTG). Of these, DTG and BIC perform better against a wide range of resistance mutations than other INSTIs. Nevertheless, drug-resistant combinations of mutations have begun to emerge against all DAPYs and INSTIs, attributable in part to non-adherence. New dual therapies that may promote better adherence combine ETR or RPV with an INSTI and have been safer and non-inferior to more traditional triple-drug treatments. Long-acting dual- and triple-therapies combining ETR or RPV with INSTIs are under study and may further improve adherence. Here, highly resistant emergent mutations and efficacy data on these novel treatments are reviewed. Overall, ETR or RPV, in combination with INSTIs, may be treatments of choice as long-term maintenance therapies that optimize efficacy, adherence, and safety.

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Section: Dapy/insti Dual Therapiesmentioning

confidence: 99%

“…The virologic failure of patients on ETR, RPV, and cARTs has been attributed in part to regimen non-adherence [40,41,50,60,64,65]. [42,[66][67][68]. Important single bonds with broad rotational flexibility are shown in red or with partial flexibility in blue.…”

Section: Introductionmentioning

confidence: 99%

Non-Nucleoside Reverse Transcriptase Inhibitors Join Forces with Integrase Inhibitors to Combat HIV

Himmel¹,

Arnold

2020

Pharmaceuticals

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“…The development of flow chemistry over the past few decades has led to improvements in synthesis, [1][2][3][4][5][6][7][8] catalysis, [9][10][11][12][13] reaction screening, 14 scale up, 15,16 and quality control. [17][18][19] Flow syntheses applied to bulk polymerizations have shown better control in reaction kinetics and have improved product quality.…”

Section: Introductionmentioning

confidence: 99%

Surfactant‐free synthesis of poly (styrene‐co‐acrylamide) monodisperse nanoparticles using hybrid flow‐to‐batch chemistry

Antoniv

Chang

AlJabri

et al. 2020

J of Applied Polymer Sci

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We have demonstrated a hybrid flow-to-batch process for synthesizing monodisperse poly(styrene-co-acrylamide) nanoparticles via a surfactant-free emulsion radical polymerization. The flow-to-batch synthesized nanoparticles have a smaller average particle size, tighter particle size distribution, higher molecular weight, and lower molecular weight distribution compared to conventionally batch-synthesized nanoparticles. Our results also indicate that the flow-to-batch synthesized nanoparticles have more hydrophilic acrylamide segments on the particle surface than the batch-synthesized nanoparticles. These results demonstrate that a flow synthesis process can improve the quality of nanoparticles due to the efficient mixing and heat transfer in a flow reactor and simplify the scale up of nanoparticle synthesis in a conventional chemistry lab.

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“…Compared with the first generation of integrase inhibitors, raltegravir and elvitegravir, dolutegravir possesses a higher barrier for developing resistance, as well as that the clinical efficacy for AIDS treatment is better than raltegravir . Recently, there is a great need for process research for the forthcoming industrial manufacture. Hence, an efficient synthetic route of dolutegravir is urgently needed.…”

Section: Introductionmentioning

confidence: 99%