nirmatrelvir   Click here for help

GtoPdb Ligand ID: 11503

Synonyms: example E61 [WO2021250648A1] | Paxlovid® (nirmatrelvir + ritonavir) | PF-07321332 | PF07321332
Approved drug
nirmatrelvir is an approved drug (UK MHRA (2021), EMA (2022))
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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2D Structure
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Physico-chemical Properties
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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
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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
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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'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. In the US Paxlovid is only available under emergency use authorisation (as of Feb. 2022).
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.