molnupiravir   Click here for help

GtoPdb Ligand ID: 10737

Synonyms: EIDD-2801 | EIDD2801 | Lagevrio® | MK-4482 | MK4482
Approved drug
molnupiravir is an approved drug (UK (2021))
Compound class: Synthetic organic
Comment: Molnupiravir (EIDD-2801, MK-4482) is an oral, broad-spectrum antiviral drug [1,8]. The proposed INN molnupiravir was released by the WHO in a special release to cover COVID-related therapeutics in October 2020 (Proposed INN: List 124-COVID-19). Chemically molnupiravir is the isopropylester prodrug of the ribonucleoside analogue β-D-N4-hydroxycytidine (EIDD-1931, or N-hydroxycytidine) [10-11]. Functionally, the active form of molnupiravir is incorporated into the virus' RNA by the viral RNA-dependent RNA polymerase (RdRp) during replication, which results in lethal mutagenesis [4]. Molnupiravir was originally designed by Emory University scientists to inhibit replication of influenza virus. It has subsequently been tested for activity against other RNA viruses, including pandemic SARS-CoV-2, SARS-CoV and MERS-CoV [14]. Molnupiravir was being progressed for COVID-19 in a collaboration between Ridgeback Biotherapeutics and Merck. In vivo therapeutic and prophylactic potential was reported in a peer reviewed manuscript in February 2021 [12].
There is concern that molnupiravir may induce mutations in the host, based on evidence from mammalian cell culture experiments [13] and using the Ames test (bacteria).
2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 6
Hydrogen bond donors 4
Rotatable bonds 6
Topological polar surface area 143.14
Molecular weight 329.12
XLogP 0
No. Lipinski's rules broken 0
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Canonical SMILES ONc1ccn(c(=O)n1)[C@@H]1O[C@@H]([C@H]([C@H]1O)O)COC(=O)C(C)C
Isomeric SMILES ONc1ccn(c(=O)n1)[C@@H]1O[C@@H]([C@H]([C@H]1O)O)COC(=O)C(C)C
InChI InChI=1S/C13H19N3O7/c1-6(2)12(19)22-5-7-9(17)10(18)11(23-7)16-4-3-8(15-21)14-13(16)20/h3-4,6-7,9-11,17-18,21H,5H2,1-2H3,(H,14,15,20)/t7-,9-,10-,11-/m1/s1
No information available.
Summary of Clinical Use Click here for help
A first-in-human safety, tolerability and pharmacokinetics RCT investigating molnupiravir/EIDD-2801 (in healthy volunteers) in the UK began in mid-April 2020 and recruitment of US participants began a few weeks later. Although Phase 1 safety results have not yet been published, Ridgeback Biotherapeutics have announced via press release (June 19, 2020) that EIDD-2801 is safe in humans at predicted therapeutic doses. At this time Ridgeback advised that they would launch two Phase 2 clinical trials in recently symptomatic, newly diagnosed COVID-19 patients (separate trials for newly hospitalised and newly diagnosed non-hospitalised patient groups) [2]. These studies recruited participants in the US and in the UK. In April 2021, Merck announced that they were discontinuing development of molnupiravir in hospitalised patients after a predicted lack of efficacy became evident from the clinical trial. In contrast a company press release from Merck on 1st October 2021 [6], revealed that so significant was the clinical benefit of molnupiravir in at-risk, non-hospitalized adult patients with mild-to-moderate COVID-19, the FDA Data and Safety Monitoring Board recommended stopping the trial early, viewing it unethical to proceed. At a planned interim analysis of data collected from an initial set of >750 participants (recruited between May and early August), molnupiravir reduced the risk of hospitalisation or death by ~50% in patients with confirmed mild-to-moderate COVID-19 and at least one risk factor associated with poor disease outcome (on a regimen of 4 tablets of drug or placebo, twice daily for 5 consecutive days). However, treatment in a subsequent cohort of ~650 participants (recruited between August and early October) was found to be less effective than previously thought. In response to the original efficacy data, Ridgeback/Merck proceeded to submit applications for approval to various national drug regulatory agencies. Molnupiravir's first approval was issued by the UK's MHRA on 4th Nov. 2021, as a treatment for recently diagnosed SARS-CoV-2 infection in non-hospitalised individuals who have at least one risk factor for developing severe illness [9]. The US FDA recommended molnupiravir for EUA in late November 2021. Approvals by other national regulatory agencies are pending.
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT04392219 COVID-19 First In Human Study to Evaluate Safety, Tolerability, and Pharmacokinetics of EIDD-2801 in Healthy Volunteers Phase 1 Interventional Ridgeback Biotherapeutics, LP
NCT04405739 The Effect of EIDD-2801 on Viral Shedding of SARS-CoV-2 (COVID-19) Phase 2 Interventional Ridgeback Biotherapeutics, LP
NCT04405570 A Safety, Tolerability and Efficacy of EIDD-2801 to Eliminate Infectious Virus Detection in Persons With COVID-19 Phase 2 Interventional Ridgeback Biotherapeutics, LP 7
NCT04575584 Efficacy and Safety of Molnupiravir (MK-4482) in Hospitalized Adult Participants With COVID-19 (MK-4482-001) Phase 2/Phase 3 Interventional Merck Sharp & Dohme Corp.
NCT04746183 AGILE (Early Phase Platform Trial for COVID-19) Phase 1/Phase 2 Interventional University of Liverpool This is the AGILE CST-2 study that was carried out in the UK between November 2020 and March 2022. 5
NCT04575597 Efficacy and Safety of Molnupiravir (MK-4482) in Non-Hospitalized Adult Participants With COVID-19 (MK-4482-002) Phase 2/Phase 3 Interventional Merck Sharp & Dohme Corp. MOVe-OUT trial: A press release from Merck in Oct 2021 indicated that at a planned interim analysis molnupiravir reduced the risk of hospitalisation or death by approximately 50% in patients with confirmed mild-to-moderate COVID-19 and at least one risk factor associated with poor disease outcome. The clinical benefit was evident across viral variants such as Gamma, Delta, and Mu. 3
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