Nirmatrelvir is an antiviral drug developed by Pfizer as an orally active 3C-like protease inhibitor. It is part of the nirmatrelvir/ritonavir combination and is marketed under the brand name Paxlovid.
Coronavirus proteases cleave at multiple sites in the viral polyprotein, usually after glutamine residues. Early studies on related human rhinoviruses showed that flexible glutamine side chains can be replaced by rigid pyrrolidone. These drugs were further developed for other diseases, including SARS, before the COVID-19 pandemic. In 2018, GC376 (a prodrug GC373) was used to treat a previously 100% fatal feline coronavirus disease, feline infectious peritonitis, caused by feline coronavirus. Nirmatrelvir and GC373 are both peptide mimetics that share the above-mentioned pyrrolidone at the P1 position and are competitive inhibitors; however, they use nitriles and aldehydes, respectively, to bind the catalytic cysteine. Pfizer studied two series of compounds with nitriles and benzothiazol-2-yl ketones as reactive groups, ultimately settling on nitriles.
Nirmatrelvir was developed by modifying the early clinical candidate lufotrelvir, which is also a covalent protease inhibitor, but its warhead is a phosphate prodrug of a hydroxyketone. Lufotrelvir requires intravenous administration, limiting its use to hospital settings. Stepwise modification of tripeptide protein mimetics resulted in nimatravir suitable for oral administration. Key changes include reducing the number of hydrogen bond donors and reducing the number of rotatable bonds by introducing a rigid bicyclic ring Unconventional amino acids (specifically a "fused cyclopropyl ring with two methyl groups"), which mimic the leucine residue found in earlier inhibitors. This residue was previously used in the synthesis of boceprevir. Using combinatorial chemistry (hybrid combinatorial substrate library technology), the tertiary leucine (abbreviation: Tle) used at the P3 position of nimaprevir was identified for the first time as the best non-classical amino acid in potential drugs targeting SARS-CoV-2 3C-like protease. ).
However, leucine-like residues cause nearby loss of contact with glycine. To compensate, Pfizer tried adding methanesulfonamide, acetamide, and trifluoroacetamide, and found that trifluoroacetamide had excellent oral bioavailability.
Chemistry and Pharmacology
Full details of the synthesis of nirmatrelvir have been published for the first time by Pfizer scientists.
In the penultimate step, the synthesized homochiral amino acid is coupled to the homochiral aminoamide using the water-soluble carbodiimide EDCI as the coupling agent. The resulting intermediate is then treated with Burgess' reagent to dehydrate the amide group to the product nitrile.
Nirmatrelvir is a covalent inhibitor that binds directly to the catalytic cysteine (Cys145) residue of caspases.
In the co-packaged drug nirmatrelvir/ritonavir, ritonavir slows the metabolism of nirmatrelvir through cytochrome enzyme inhibition, thereby increasing circulating concentrations of the primary drug. This effect is also used in HIV therapy, where ritonavir is combined with another protease inhibitor to similarly enhance its pharmacokinetics.
In November 2021, Pfizer signed a licensing agreement with the United Nations-backed Drug Patent Pool, allowing nirmatrelvir to be produced and sold in 95 countries. Pfizer said the agreement would allow local drug manufacturers to produce the pills "with the goal of promoting greater access to the global population". However, the agreement excludes several countries with major COVID-19 outbreaks, including Brazil, China, Russia, Argentina and Thailand.
The research leading to nirmatrelvir began on March 16, 2020, when Pfizer officially launched a project at its Cambridge, Massachusetts, facility to develop an antiviral drug to treat COVID-19. [ On July 22, 2020, Pfizer chemists were able to synthesize nirmatrelvir for the first time, although the significance of that moment was unclear at the time, as it was just one of 20 drug candidates synthesized that week. On September 1, 2020, Pfizer completed a pharmacokinetic study in rats demonstrating that nimaprevir can be administered orally. The actual synthesis of drugs used in laboratory studies and clinical trials occurs at Pfizer's facility in Groton, Connecticut.
In February 2021, Pfizer initiated the company's first Phase I trial of PF-07321332 (nirmatrelvir) at its clinical research unit in New Haven, Connecticut. According to Chemistry & Engineering News , the drug “went from an idea to the first human clinical trial in 12 months—an incredible speed to deliver a custom drug candidate.