Coronaviral
proteases cleave multiple sites in the viral
polyprotein, usually after there are
glutamine residues. Early work on related human
rhinoviruses showed that the flexible glutamine side chain in inhibitors could be replaced by a rigid
pyrrolidone.[9][10] These drugs had been further developed prior to the
COVID-19 pandemic for other diseases including
SARS.[11] The utility of targeting the 3CL protease in a real world setting was first demonstrated in 2018 when
GC376 (a
prodrug of GC373) was used to treat the previously 100% lethal cat coronavirus disease,
feline infectious peritonitis, caused by
feline coronavirus.[12] Nirmatrelvir and GC373 are both
peptidomimetics, share the aforementioned
pyrrolidone in P1 position and are competitive inhibitors. They use a
nitrile and an
aldehyde respectively to bind the catalytic
cysteine.[13][14] Pfizer investigated two series of compounds, with nitrile and benzothiazol-2-yl ketone as the reactive group, respectively, and in the end settled on using nitrile.[15]
Nirmatrelvir was developed by modification of the earlier clinical candidate
lufotrelvir,[16][full citation needed][17] which is also a covalent protease inhibitor but its active element is a phosphate
prodrug of a
hydroxyketone. Lufotrelvir needs to be administered
intravenously limiting its use to a hospital setting. Stepwise modification of the
tripeptidepeptidomimetic led to nirmatrelvir, which is suitable for
oral administration.[3] Key changes include a reduction in the number of
hydrogen bond donors, and the
number of rotatable bonds by introducing a rigid bicyclic
non-canonical amino acid (specifically, a "fused cyclopropyl ring with two methyl groups"[15]), which mimics the
leucine residue found in earlier inhibitors. This residue had previously been used in the synthesis of
boceprevir.[18] Tert-leucine (abbreviation: Tle) used in the P3 position of nirmatrelvir was identified first as optimal non-canonical amino acid in potential drug targeting SARS-CoV-2 3C-like protease using
combinatorial chemistry (hybrid combinatorial substrate library technology).[19][20]
The leucine-like residue resulted in loss of a nearby contact with a
glutamine on the 3C-like protease.[15] To compensate Pfizer tried adding methane
sulfonamide,
acetamide, and
trifluoroacetamide and discovered that of the three, trifluoroacetamide resulted in superior oral bioavailability.[15]
Chemistry and pharmacology
Full details of the synthesis of nirmatrelvir were first published by scientists from Pfizer.
In the co-packaged medication
nirmatrelvir/ritonavir,
ritonavir serves to slow the metabolism of nirmatrelvir via
cytochrome enzyme inhibition, thereby increasing the circulating concentration of the main drug.[22] This effect is also used in
HIV therapy, where ritonavir is used in combination with another
protease inhibitor to similarly enhance their pharmacokinetics.[23]
Society and culture
Licensing
In November 2021, Pfizer signed a license agreement with the
United Nations–backed
Medicines Patent Pool to allow nirmatrelvir to be manufactured and sold in 95 countries.[24] Pfizer stated that the agreement will allow local medicine manufacturers to produce the pill "with the goal of facilitating greater access to the global population". The deal excludes several countries with major COVID-19 outbreaks including Brazil, China, Russia, Argentina, and Thailand.[25][26]
The research that led to nirmatrelvir began in March 2020, when Pfizer formally launched a project at its
Cambridge, Massachusetts site to develop antiviral drugs for treating COVID-19.[15] In July 2020, Pfizer chemists were able to synthesize nirmatrelvir for the first time.[15] In September 2020, Pfizer completed a
pharmacokinetic study in rats which suggested that nirmatrelvir could be administered orally.[15] The actual synthesis of the drug for laboratory research and for clinical trials was carried out at Pfizer's
Groton, Connecticut site.[28]
A study published in March 2023 reported that treatment with nirmatrelvir within five days of initial infection reduced the risk of
long COVID relative to patients who did not receive Paxlovid.[30]
^Clinical trial number NCT04535167 for "First-In-Human Study To Evaluate Safety, Tolerability, And Pharmacokinetics Following Single Ascending And Multiple Ascending Doses of PF-07304814 In Hospitalized Participants With COVID-19 " at
ClinicalTrials.gov
^Njoroge FG, Chen KX, Shih NY, Piwinski JJ (January 2008). "Challenges in modern drug discovery: a case study of boceprevir, an HCV protease inhibitor for the treatment of hepatitis C virus infection". Accounts of Chemical Research. 41 (1): 50–59.
doi:
10.1021/ar700109k.
PMID18193821.
S2CID2629035.
^World Health Organization (2022). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 88". WHO Drug Information. 36 (3).
hdl:10665/363551.