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Efficient synthesis of antiviral agent uprifosbuvir enabled by new synthetic methods.

ABSTRACT: An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield. This concise synthesis was achieved by development of several synthetic methods: (1) complexation-driven selective acyl migration/oxidation; (2) BSA-mediated cyclization to anhydrouridine; (3) hydrochlorination using FeCl₃/TMDSO; (4) dynamic stereoselective phosphoramidation using a chiral nucleophilic catalyst. The new route improves the yield of uprifosbuvir 50-fold over the previous manufacturing process and expands the tool set available for synthesis of antiviral nucleotides.

SUBMITTER: Klapars A

PROVIDER: S-EPMC8261776 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Efficient synthesis of antiviral agent uprifosbuvir enabled by new synthetic methods.

Klapars Artis A Chung John Y L JYL Limanto John J Calabria Ralph R Campeau Louis-Charles LC Campos Kevin R KR Chen Wenyong W Dalby Stephen M SM Davis Tyler A TA DiRocco Daniel A DA Hyde Alan M AM Kassim Amude M AM Larsen Mona Utne MU Liu Guiquan G Maligres Peter E PE Moment Aaron A Peng Feng F Ruck Rebecca T RT Shevlin Michael M Simmons Bryon L BL Song Zhiguo Jake ZJ Tan Lushi L Wright Timothy J TJ Zultanski Susan L SL

Chemical science 20210519 26

An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield. This concise synthesis was achieved by development of several synthetic methods: (1) complexation-driven selective acyl migration/oxidation; (2) BSA-mediated cyclization to anhydrouridine; (3) hydrochlorination using FeCl<sub>3</sub>/TMDSO; (4) dynamic stereoselective phosphoramidation using a chiral nucleophilic catalyst. The new route improves the yield of up ...[more]

PMID: 34276931

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Project description:BackgroundOne of the most prominent opioid analgesics in the United States is the high potency agonist fentanyl. It is used in the treatment of acute and chronic pain and as an anesthetic adjuvant. When used inappropriately, however, ingestion of just a few milligrams of fentanyl or other synthetic opioid can cause opioid-induced respiratory depression (OIRD), often leading to death. Currently, the treatment of choice for OIRD is the opioid receptor antagonist naloxone. Recent reports, however, suggest that higher doses or repeated dosing of naloxone (due to recurrence of respiratory depression) may be required to reverse fully fentanyl-induced respiratory depression, rendering this treatment inadequate. To combat this synthetic opioid overdose crisis, this research aims at identifying a novel opioid reversal agent with enhanced efficacy towards fentanyl and other synthetic opioids.MethodsA series of naltrexone analogues were characterized for their ability to antagonize the effects of fentanyl in vitro utilizing a modified forskolin-induced cAMP accumulation assay. Lead analogue 29 was chosen to undergo further PK studies, followed by in vivo pharmacological analysis to determine its ability to antagonize opioid-induced antinociception in the hot plate assay.ResultsA series of potent MOR antagonists were identified, including the highly potent analogue 29 (IC50 = 2.06 nM). Follow-up PK studies revealed 29 to possess near 100% bioavailability following IP administration. Brain concentrations of 29 surpassed plasma concentrations, with an apparent terminal half-life of ~ 80 min in mice. In the hot plate assay, 29 dose-dependently (0.01-0.1 mg/kg; IP) and fully antagonized the antinociception induced by oxycodone (5.6 mg/kg; IP). Furthermore, the dose of 29 that is fully effective in preventing oxycodone-induced antinociception (0.1 mg/kg) was ineffective against locomotor deficits caused by the KOR agonist U50,488.ConclusionsMethods have been developed that have utility to identify enhanced rescue agents for the treatment of OIRD. Analogue 29, possessing potent MOR antagonist activity in vitro and in vivo, provides a promising lead in our search for an enhanced synthetic opioid rescue agent.

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Efficient synthesis of antiviral agent uprifosbuvir enabled by new synthetic methods.

Publications

Efficient synthesis of antiviral agent uprifosbuvir enabled by new synthetic methods.

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