Identification

Summary

PF-07321332 is an oral protease inhibitor in clinical trials for the treatment of SARS-CoV-2 infections.

Generic Name
PF-07321332
DrugBank Accession Number
DB16691
Background

PF-07321332, by Pfizer, is an orally bioavailable 3C-like protease (3CLPRO) inhibitor that is the subject of clinical trial NCT04756531.4 This drug is being investigated for safety, tolerability, and pharmacokinetics before moving on to studies of efficacy in the treatment or prophylaxis of COVID-19.4,5 3CLPRO is responsible for cleaving polyproteins 1a and 1ab of SARS-CoV-2.1 Without the activity of the SARS-CoV-2 3CLPRO, nonstructural proteins (including proteases) cannot be released to perform their functions, inhibiting viral replication.1,2,3

In 2020, Pfizer was investigating another potential treatment for SARS-CoV-2, PF-07304814.5 Both drugs were inhibitors of SARS-CoV-2 3CLPRO, but PF-07321332 has the advantage of being orally bioavailable.5 If successful, PF-07321332 can be prescribed to patients before they require hospitalization, while PF-07304814 requires intravenous administration in hospital.5

Type
Small Molecule
Groups
Investigational
Structure
Thumb
Weight
Average: 499.535
Monoisotopic: 499.240639019
Chemical Formula
C23H32F3N5O4
Synonyms
Not Available

Pharmacology

Indication

PF-07321332 is currently undergoing clinical trials for safety and efficacy in the treatment and prevention of COVID-19.5

Pharmacology
Reduce drug development failure rates
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Contraindications & Blackbox Warnings
Contraindications
Avoid life-threatening adverse drug events
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Avoid life-threatening adverse drug events & improve clinical decision support.
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Pharmacodynamics

Not Available

Mechanism of action

PF-07321332 is an inhibitor of a cysteine residue in the 3C-like protease (3CLPRO) of SARS-CoV-2.5 This cysteine is responsible to the activity of the 3CLPRO of SARS-CoV-2 and potentially other members of the coronavirus family.1,2 The 3CLPRO, also known as the main protease or non structural protein 5, is responsible for cleaving polyproteins 1a and 1ab.1 These polyproteins contain the 3CLPRO itself, a papain-like (PL) cysteine protease, and 14 other nonstructural proteins.3 Without the activity of the 3CLPRO, nonstructural proteins (including proteases) cannot be released to perform their functions, inhibiting viral replication.1,2,3

TargetActionsOrganism
AReplicase polyprotein 1ab
inhibitor
SARS-CoV-2
Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Not Available

Half-life

Not Available

Clearance

Not Available

Adverse Effects
Adverseeffects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
Not Available

Categories

Drug Categories
Classification
Not classified
Affected organisms
  • SARS-CoV-2

Chemical Identifiers

UNII
7R9A5P7H32
CAS number
Not Available
InChI Key
LIENCHBZNNMNKG-OJFNHCPVSA-N
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
IUPAC Name
(1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
SMILES
[H][C@]12CN([C@H](C(=O)N[C@@H](C[C@]3([H])CCNC3=O)C#N)[C@@]1([H])C2(C)C)C(=O)[C@@H](NC(=O)C(F)(F)F)C(C)(C)C

References

General References
  1. Ionescu MI: An Overview of the Crystallized Structures of the SARS-CoV-2. Protein J. 2020 Dec;39(6):600-618. doi: 10.1007/s10930-020-09933-w. Epub 2020 Oct 24. [Article]
  2. Muramatsu T, Takemoto C, Kim YT, Wang H, Nishii W, Terada T, Shirouzu M, Yokoyama S: SARS-CoV 3CL protease cleaves its C-terminal autoprocessing site by novel subsite cooperativity. Proc Natl Acad Sci U S A. 2016 Nov 15;113(46):12997-13002. doi: 10.1073/pnas.1601327113. Epub 2016 Oct 31. [Article]
  3. Xiong M, Su H, Zhao W, Xie H, Shao Q, Xu Y: What coronavirus 3C-like protease tells us: From structure, substrate selectivity, to inhibitor design. Med Res Rev. 2021 Jan 18. doi: 10.1002/med.21783. [Article]
  4. Clinical Trials: NCT04756531 [Link]
  5. Pfizer Press Release: PFIZER INITIATES PHASE 1 STUDY OF NOVEL ORAL ANTIVIRAL THERAPEUTIC AGENT AGAINST SARS-COV-2 [Link]
Wikipedia
3C-like_protease

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3RecruitingPreventionCoronavirus Disease 2019 (COVID‑19)1
3RecruitingTreatmentCoronavirus Disease 2019 (COVID‑19)2
1CompletedBasic ScienceCoronavirus Disease 2019 (COVID‑19) / Healthy Subjects (HS)1
1CompletedBasic ScienceDeteriorating renal function1
1CompletedBasic ScienceHealthy Subjects (HS)1
1CompletedOtherHealthy Subjects (HS)1
1Not Yet RecruitingBasic ScienceHealthy Subjects (HS)1
1RecruitingBasic ScienceCoronavirus Disease 2019 (COVID‑19) / Healthy Subjects (HS)1
1RecruitingBasic ScienceHealthy Subjects (HS)1
1RecruitingBasic ScienceHepatic Impairment1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0277 mg/mLALOGPS
logP2.12ALOGPS
logP0.44ChemAxon
logS-4.3ALOGPS
pKa (Strongest Acidic)7.1ChemAxon
pKa (Strongest Basic)-1.6ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area131.4 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity117.52 m3·mol-1ChemAxon
Polarizability47.09 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Drugtargets2
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Kind
Protein
Organism
SARS-CoV-2
Pharmacological action
Yes
Actions
Inhibitor
General Function
Replicase polyprotein 1ab Multifunctional protein involved in the transcription and replication of viral RNAs. Contains the proteinases responsible for the cleavages of the polyprotein.
Specific Function
Atp binding
Gene Name
rep
Uniprot ID
P0DTD1
Uniprot Name
Replicase polyprotein 1ab
Molecular Weight
794051.285 Da
References
  1. Ionescu MI: An Overview of the Crystallized Structures of the SARS-CoV-2. Protein J. 2020 Dec;39(6):600-618. doi: 10.1007/s10930-020-09933-w. Epub 2020 Oct 24. [Article]
  2. Pfizer Press Release: PFIZER INITIATES PHASE 1 STUDY OF NOVEL ORAL ANTIVIRAL THERAPEUTIC AGENT AGAINST SARS-COV-2 [Link]

Drug created at April 27, 2021 04:24 / Updated at April 30, 2021 13:08