Toward a Practical, Two-Step Process for Molnupiravir: Direct Hydroxamination of Cytidine Followed by Selective Esterification

Paymode, Dinesh J.; Vasudevan, N.; Ahmad, Saeed; Kadam, Appasaheb L.; Cardoso, Flávio S. P.; Burns, Justina M.; Cook, Daniel W.; Stringham, Rodger W.; Snead, David R.

doi:10.1021/acs.oprd.1c00033

Cited by 36 publications

(64 citation statements)

References 12 publications

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“…Furthermore, while the signals for the H1 hydroxyl protons are shown almost in the same region at 2.33-2.90 ppm, the signals for the other hydroxyl protons, together with the signals for the NH protons, vary from 2.87 to 7.88 ppm (Table 7). Notably, the calculated 1 H NMR spectra of both the keto-oxime and hydroxyl-oxime tautomers agree with the experimental one [26]. Since the experimental spectrum was recorded in methanol-d 4 , thus, vanishing plausible signals from the hydroxyl and amine hydrogens, it is impossible to clearly attribute the exact tautomer of the mentioned two.…”

Section: Resultssupporting

confidence: 70%

Computational Analysis of Molnupiravir

Sharov

Burkhanova

Tok

et al. 2022

IJMS

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In this work, we report in-depth computational studies of three plausible tautomeric forms, generated through the migration of two acidic protons of the N4-hydroxylcytosine fragment, of molnupiravir, which is emerging as an efficient drug to treat COVID-19. The DFT calculations were performed to verify the structure of these tautomers, as well as their electronic and optical properties. Molecular docking was applied to examine the influence of the structures of tautomers on a series of the SARS-CoV-2 proteins. These tautomers exhibited the best affinity behavior (−9.90, −7.90, and −9.30 kcal/mol, respectively) towards RdRp-RTR and Nonstructural protein 3 (nsp3_range 207–379-MES).

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Section: Resultssupporting

confidence: 70%

Computational Analysis of Molnupiravir

Sharov

Burkhanova

Tok

et al. 2022

IJMS

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“…Uridine is a costly starting material. Therefore, some new patented/non patented routes for the synthesis of molnupiravir utilizing cheaper starting materials (cytidine) have also been developed [31][32][33]60,61]. Our patent search also revealed IN202121014827A [62], IN202121005152A [63], and IN202141011933A [64], which also cover processes for preparing molnupiravir.…”

Section: Expert Opinionmentioning

confidence: 99%

Discovery, Development, and Patent Trends on Molnupiravir: A Prospective Oral Treatment for COVID-19

Imran

Arora

Asdaq³

et al. 2021

Molecules

149

157

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The COVID-19 pandemic needs no introduction at present. Only a few treatments are available for this disease, including remdesivir and favipiravir. Accordingly, the pharmaceutical industry is striving to develop new treatments for COVID-19. Molnupiravir, an orally active RdRp inhibitor, is in a phase 3 clinical trial against COVID-19. The objective of this review article is to enlighten the researchers working on COVID-19 about the discovery, recent developments, and patents related to molnupiravir. Molnupiravir was originally developed for the treatment of influenza at Emory University, USA. However, this drug has also demonstrated activity against a variety of viruses, including SARS-CoV-2. Now it is being jointly developed by Emory University, Ridgeback Biotherapeutics, and Merck to treat COVID-19. The published clinical data indicate a good safety profile, tolerability, and oral bioavailability of molnupiravir in humans. The patient-compliant oral dosage form of molnupiravir may hit the market in the first or second quarter of 2022. The patent data of molnupiravir revealed its granted compound patent and process-related patent applications. We also anticipate patent filing related to oral dosage forms, inhalers, and a combination of molnupiravir with marketed drugs like remdesivir, favipiravir, and baricitinib. The current pandemic demands a patient compliant, safe, tolerable, and orally effective COVID-19 treatment. The authors believe that molnupiravir meets these requirements and is a breakthrough COVID-19 treatment.

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“…This four-step route used low-cost reagents to produce molnupiravir in an overall 44% yield 10 . Recent inquiry has shown that cytidine is available on the commercial marketplace in the multi-metric ton scale 11 .…”

Section: Introductionmentioning

confidence: 99%

Cost of Goods Analysis Facilitates an Integrated Approach to Identifying Alternative Synthesis Methodologies for Lower Cost Manufacturing of the COVID-19 Antiviral Molnupiravir

Peterson

Paria

Deshpande³

et al. 2022

Gates Open Res

Self Cite

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Orally delivered drugs offer significant benefits in the fight against viral infections, and cost-effective production is critical to their impact on pandemic response in low- and middle-income countries. One example, molnupiravir, a COVID-19 therapy developed by Emory, Ridgeback, and Merck & Co., had potential to benefit from significant cost of goods (COGs) reductions for its active pharmaceutical ingredient (API), including starting materials. A holistic approach to identifying, developing, and evaluating optimized synthetic routes, which includes detailed COGs modeling, provides a rapid means to increase the availability, uptake and application of molnupiravir and other antivirals in global markets. Identification and development of alternate processes for the synthesis of molnupiravir has been conducted by the Medicines for All Institute at Virginia Commonwealth University (M4ALL) and the Green and Turner Labs at the University of Manchester. Both groups developed innovative processes based on synthetic route design and biocatalysis aimed at lowering costs and improving global access. The authors then performed COGs modeling to assess cost saving opportunities. This included a focus on manufacturing environments and facilities amenable to global public health and the identification of key parameters using sensitivity analyses. While all of the evaluated routes provide efficiency benefits, the best options yielded 3-6 fold API COGs reductions leading to treatment COGs as low as <$3/regimen. Additionally, key starting materials and cost drivers were quantified to evaluate the robustness of the savings. Finally, COGs models can continue to inform the focus of future development efforts on the most promising routes for additional cost savings. While the full price of a treatment course includes other factors, these alternative API synthetic approaches have significant potential to help facilitate broader access in low- and middle-income countries. As other promising therapeutics are developed, a similar process could enable rapid cost reductions while enhancing global access.

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Toward a Practical, Two-Step Process for Molnupiravir: Direct Hydroxamination of Cytidine Followed by Selective Esterification

Cited by 36 publications

References 12 publications

Computational Analysis of Molnupiravir

Computational Analysis of Molnupiravir

Discovery, Development, and Patent Trends on Molnupiravir: A Prospective Oral Treatment for COVID-19

Cost of Goods Analysis Facilitates an Integrated Approach to Identifying Alternative Synthesis Methodologies for Lower Cost Manufacturing of the COVID-19 Antiviral Molnupiravir

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