nirmatrelvir   Click here for help

GtoPdb Ligand ID: 11503

Synonyms: example E61 [WO2021250648A1] | Paxlovid® (nirmatrelvir + ritonavir) | PF-07321332 | PF07321332
Approved drug PDB Ligand
nirmatrelvir is an approved drug (UK MHRA (2021), EMA (2022), FDA (2023))
Compound class: Synthetic organic
Comment: PF-07321332 (nirmatrelvir) is an oral antiviral clinical lead. It is a covalent inhibitor of SARS-CoV-2 Mpro (main protease, 3CLpro) that binds to cysteine145 within the enzyme's catalytic domain [4]. Mpro is essential for coronavirus replication. Inhibiting Mpro actvity blocks replication at an early stage in the virus' life cycle. Due to structural similarities between the Mpro's of other coronavirusus, PF-07321332 offers the potential of pan-coronavirus activity. In vitro it is suggested to inhibit replication of CoV-2 variants including delta and omicron.

PF-07321332 is structurally similar to ML1000. Prior to peer-reviewed name-to-structure disclosure, we obtained the structure represented here from an online report by Dr Bethany Halford who attended a session by Dafydd Owen (Pfizer) at the ACS Spring 2021 meeting (@beth_halford image on Twitter) which rendered the SMILES string N#C[C@H](C[C@@H]1CCNC1=O)NC(=O)[C@H]1N(C[C@H]2[C@@H]1C2(C)C)C(=O)[C@H](C(C)(C)C)NC(=O)C(F)(F)F. PF-07321332's chemical structure was formally disclosed in Owen et al's Science article in November 2021 [3], and this confirmed the structure that was obtained from the ACS meeting.
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 9
Hydrogen bond donors 3
Rotatable bonds 11
Topological polar surface area 131.4
Molecular weight 499.24
XLogP 1.39
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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Canonical SMILES N#C[C@H](C[C@@H]1CCNC1=O)NC(=O)[C@H]1N(C[C@H]2[C@@H]1C2(C)C)C(=O)[C@H](C(C)(C)C)NC(=O)C(F)(F)F
Isomeric SMILES N#C[C@H](C[C@@H]1CCNC1=O)NC(=O)[C@H]1N(C[C@H]2[C@@H]1C2(C)C)C(=O)[C@H](C(C)(C)C)NC(=O)C(F)(F)F
InChI InChI=1S/C23H32F3N5O4/c1-21(2,3)16(30-20(35)23(24,25)26)19(34)31-10-13-14(22(13,4)5)15(31)18(33)29-12(9-27)8-11-6-7-28-17(11)32/h11-16H,6-8,10H2,1-5H3,(H,28,32)(H,29,33)(H,30,35)/t11-,12-,13-,14-,15-,16+/m0/s1
InChI Key LIENCHBZNNMNKG-OJFNHCPVSA-N
No information available.
Summary of Clinical Use Click here for help
Nirmatrelvir (PF-07321332) was progressed to clinical trial to determine safety and efficacy as a treatment for COVID-19. Phase 1 (NCT04756531) results were published in November 2021 [3]. Click here to link to ClinicalTrials.gov's full list of PF-07321332 studies.

A few days after the Phase 1 results were published, Pfizer announced (via press release) that interim analysis from their Phase 3 EPIC-HR study (NCT04960202), indicated that PF-07321332 (in combination with ritonavir) reduced the risk of hospitalisation or death by almost 90% in patients who were at high risk of progressing to severe illness, and who were treated within 3 days of symptom onset. Final results of NCT04960202 were formally published in February 2022, confirming the preliminary efficacy [1]. This study found that PF-07321332/ritonavir treatment reduced viral load in trial participants (compared to placebo), which suggests the potential for reduced transmission.

Ritonavir is included in the dosing regimen to inhibit CYP450-mediated metabolic clearance of PF-07321332.

The UK's MHRA approved Paxlovid in December 2021, and it was granted conditional marketing authorisation by the EMA on 28th Jan. 2022. The FDA approved Paxlovid in May 2023.
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT04756531 STUDY OF PF-07321332 IN HEALTHY PARTICIPANTS Phase 1 Interventional Pfizer 3
NCT04960202 A Study of PF-07321332/Ritonavir in Nonhospitalized High Risk Adult Participants With COVID-19 Phase 2/Phase 3 Interventional Pfizer In November 2021 Pfizer announced that PF-07321332 (in combination with ) reduced the risk of hospitalisation or death by 85% in patients who were at high risk of progressing to severe illness, and who were treated within 3 days of symptom onset. The results/data have not yet been formally published.