API SYNTHESIS INTERNATIONAL: Secutrelvir

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Tuesday, 8 September 2026

Secutrelvir

Secutrelvir

CAS 2996148-73-1

MF C23H16Cl2F3N5O2 MW522.3 g/mol

2-[5-(3-chloro-4-fluorophenyl)-3-(5-chloro-3-pyridinyl)-6-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-2,4-dioxopyrimidin-1-yl]acetonitrile

2-(5-(3-chloro-4-fluorophenyl)-3-(5-chloropyridin-3-yl)-6-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetonitrile

[5-(3-chloro-4-fluorophenyl)-3-(5-chloropyridin-3-yl)-6-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]acetonitrile

[5-(3-chloro-4-fluorophenyl)-3-(5-chloropyridin-3-yl)-6-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]acetonitrile
protease inhibitor, antiviral, S-892216, S 892216, FMV68MJ8XK

Secutrelvir (also known by its developmental code S-892216) is an advanced, next-generation oral antiviral drug developed by the pharmaceutical company Shionogi. It functions as a potent SARS-CoV-2 3C-like protease (3CLpro / \(M^{\text{pro}}\)) inhibitor designed primarily for the treatment of COVID-19.

As of August 2026, the drug has entered late-stage development, with Shionogi moving into Phase 3 clinical trials to assess its efficacy and safety in patients.

Key Properties & Advantages

Unlike first-generation COVID-19 antivirals, secutrelvir was structurally optimized to address the limitations of existing treatments like Paxlovid (nirmatrelvir/ritonavir) and Shionogi’s own Xocova (ensitrelvir).

No CYP Booster Required: Secutrelvir offers 100% oral bioavailability without needing a pharmacokinetic booster like ritonavir. This dramatically reduces the risk of severe drug-drug interactions that complicate Paxlovid prescriptions.
Overcoming Viral Resistance: In laboratory assays, the compound demonstrates zero cross-resistance to viral mutants that have grown resistant to nirmatrelvir or ensitrelvir (such as those carrying E166V or M49L mutations).
High Off-Target Selectivity: It features high selectivity (>15,000-fold) over human proteases, ensuring it specifically targets viral replication without disrupting normal human cellular functions.
Broad Spectrum (Pan- β-CoV): The compound maintains high potency against a wide range of SARS-CoV-2 variants—including newer strains like Omicron JN.1—as well as other coronaviruses like SARS-CoV and MERS-CoV.

Mechanism of Action

Secutrelvir relies on a structure-based design incorporating a nitrile warhead. It enters the catalytic active site of the virus's main protease (\(M^{\text{pro}}\)) and forms a reversible covalent bond with the catalytic amino acid residue cysteine C145. By binding to this pocket, it halts the protease from cutting viral polyproteins, effectively stopping viral replication in its tracks.

[Secutrelvir (Nitrile Warhead)] 
           │
           ▼ (Reversible Covalent Binding)
   [Cysteine C145 of 3CLpro] ──► Blocked Protease Activity ──► Viral Replication Stopped

Clinical Evaluation Status

Pharmacokinetics: Clinical pharmacology data released by Shionogi Medical demonstrated excellent safety, high tolerability, and no clinically relevant food effects, meaning the drug can be taken with or without food.
Phase 3 Trials (NCT07743580 / NCT07746544): Late-stage double-blind, placebo-controlled interventional studies are assessing the drug in symptomatic, non-hospitalized COVID-19 patients who are at risk of progressing to severe illness. To qualify for the trials, patients must receive the drug within 72 hours of symptom onset

A Study of Secutrelvir in Participants With Coronavirus Disease 2019 (COVID-19) Who Are at High Risk for Progression to Severe DiseaseCTID:NCT07743580Phase:Phase 3Status:RecruitingDate:2026-08-25
Study of Secutrelvir in Participants With COVID-19CTID:NCT07746544Phase:Phase 3Status:Not yet recruitingDate:2026-08-05
A Study of S-892216 in Participants With COVID-19CTID:NCT06928051Phase:Phase 2Status:CompletedDate:2025-09-30
A Drug-drug Interaction Study of S-892216 Coadministered With Carbamazepime to Healthy Adult ParticipantsCTID:NCT06751017Phase:Phase 1Status:CompletedDate:2025-03-11

Syn

US20250092056,

https://patentscope.wipo.int/search/en/detail.jsf?docId=US451712998&_cid=P20-MTTHQ4-21870-1

Example 6

Synthesis of Compound (I-077)

Step 1 Synthesis of Compound (I-077)

Compound (I-055) (25.0 mg, 0.059 mmol), 6,6-difluoro-2-azaspiro[3.3]heptane trifluoroacetic acid salt (17.4 mg, 0.070 mmol), N, N-diisopropylethylamine (20.5 μL, 0.117 mmol), and DMF (0.5 mL) were mixed, and the solution was stirred at 60° C. for 2 hours. Water (2 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and filtered. The filtrate was concentrated, and ethyl acetate (0.05 mL), hexane (0.125 mL), and diisopropyl ether (0.125 mL) were added. The obtained precipitate was collected by filtration and washed with diisopropyl ether. The obtained solid was dried under reduced pressure to obtain Compound (I-077) (22.0 mg, 0.042 mmol, yield 72%).

¹H-NMR (CDCl ₃) δ: 2.75 (4H, t, J=12.0 Hz), 4.02 (4H, s), 4.74 (2H, s), 7.16-7.18 (2H, m), 7.32-7.35 (1H, m), 7.65 (1H, t, J=2.1 Hz), 8.43 (1H, d, J=2.3 Hz), 8.61 (1H, d, J=2.3 Hz).

LC/MS (ESI): m/z=522, RT=2.27 min, LC/MS measurement condition A

PAT

[WO2023195530A1]

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