PF-07304814 is the phosphate prodrug of PF-00835231, a coronavirus 3CL protease inhibitor originating from an earlier Pfizer antiviral research program and subsequently optimized for development against SARS-CoV-2. Lufotrelvir is its nonproprietary name, and CAS 2468015-78-1 marks the same compound.
Solubility explains why it exists. The limited aqueous solubility of PF-00835231 complicated the development of a practical intravenous formulation, prompting the design of the more water-soluble phosphate prodrug PF-07304814. A dihydrogen phosphate on its hydroxymethyl ketone fixes that: calculated logP drops to about 0.02 and the compound reaches some 50 mg/mL in water. The PF-07304814 chemical structure is otherwise unchanged, with the molecular formula C24H33N4O9P and a molecular weight of 552.52 g/mol.
The PF-07304814 structure functions as a soluble prodrug designed for intravenous delivery and subsequent enzymatic conversion to the active inhibitor PF-00835231. Catalogs drop the hyphen and file it as PF 07304814.
Application of PF-07304814
When to order the prodrug instead of the parent comes down to whether it has to dissolve.
For aqueous formulation or intravenous dosing in animals, the parent is a dead end: it resists water, and forcing it into solution means solvent systems with effects of their own. This form dissolves directly, which is why teams running infusion pharmacology or in vivo efficacy reach for it. Logistics agree: the parent ships as a dangerous good, this one does not.
It also models the phosphate-ester prodrug strategy for groups studying phosphatase-mediated activation or conversion kinetics. Combination research is a second thread: the active moiety hits protease-driven replication, remdesivir the polymerase.
One mistake is worth naming. In a biochemical assay the prodrug binds weakly next to the parent, and in cells with little phosphatase activity it looks disappointing. That is the molecule doing its job, not a defect: benchmarking potency belongs to the parent, delivery and pharmacokinetics here.
In Vitro
Measured against SARS-CoV-2 3CLpro, PF-07304814 binds with a Ki of 174 nM. Beside the parent, which inhibits the same enzyme at sub-nanomolar levels, the gap tells the story: the phosphate blocks the warhead until removed. Once cleaved, the inhibitor covers 3C-like proteases across the coronavirus family.
In Vivo
Preclinical work showed antiviral activity in a coronavirus mouse model and clean conversion, animals turning roughly 75% of a dose into the active moiety while the prodrug cleared in minutes. Pfizer PF-07304814 then became the first Mpro inhibitor to reach clinical trials: phase 1 gave 24-hour infusions of 50 to 700 mg to healthy volunteers with no serious adverse events, and a phase 1b enrolled hospitalised patients. The infusion requirement is why development narrowed: lacking an oral route, it lost out to orally active nirmatrelvir.
Biochemical and Physiological Actions
After dephosphorylation, the active moiety binds the catalytic cysteine of 3CLpro covalently but reversibly, halting cleavage of viral polyproteins into working units. The virus is left holding uncut precursors, and replication stalls before new particles can assemble.
Selectivity comes from the target itself. This protease is conserved across coronaviruses yet has no close human counterpart. PF-07304814 Pfizer development therefore focused on this pocket, leaving host enzymes largely untouched. For a drug infused into already ill patients, that margin is the point rather than a bonus.
Features and Benefits of PF-07304814
Lufotrelvir earns its place for narrow reasons:
- Water solubility the parent cannot offer, enabling intravenous dosing.
- Rapid, well-characterised conversion to the active inhibitor.
- Preclinical and phase 1 data for cross-checking results.
- No dangerous-goods restriction, unlike the parent.
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