Ibuzatrelvir
PF-07817883
CAS 2755812-39-4
| Molecular Weight | 489.49 |
|---|---|
| Formula | C21H30F3N5O5 |
- Ibuzatrelvir
- N-(Methoxycarbonyl)-3-methyl-L-valyl-(4R)-N-[(1S)-1-cyano-2-((3S)-2-oxopyrrolidin-3-yl)ethyl]-4-(trifluoromethyl)-L-prolinamide
- PF 07817883
- methyl N-[(2S)-1-[(2S,4R)-2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl]-4-(trifluoromethyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]carbamate
- KZ2X7QH2VT
Ibuzatrelvir (development code PF-07817883) is an experimental antiviral drug being developed by Pfizer for the treatment of COVID-19.[1] It is a second-generation improvement over nirmatrelvir which has a similar chemical structure.[2] One of the disadvantages of nirmatrelvir is that it has low metabolic stability and must be given in combination with ritonavir (as Paxlovid) to limit its metabolic degradation in the body.[3] Ibuzatrelvir incorporates modifications to the chemical structure of nirmatrelvir that give it enhanced oral bioavailability, so it does not require coadministration with ritonavir.[3]
Ibuzatrelvir (PF-07817883), a second-generation, orally bioavailable, is SARS-CoV-2 main protease (Mpro and 3CLpro) inhibitor with improved metabolic stability. Ibuzatrelvir has demonstrated pan-human coronavirus antiviral activity and off-target selectivity profile in vitro and in preclinical animal studies. Ibuzatrelvir is well tolerated with a safety profile similar to placebo and prevents viral infection and transmission. Ibuzatrelvir can be used to inhibit COVID-19.
SCHEME
SIDECHAIN
MAIN
PATENT
WO2021250648 PFIZER
WO2023215910
PAPER
The Pfizer scientists described ibuzatrelvir’s medicinal chemistry campaign in a Journal of Medicinal Chemistry paper that was published in April 2024 (DOI: 10.1021/acs .jmedchem.3c02469).
https://pubs.acs.org/doi/10.1021/jacsau.4c00508
Ibuzatrelvir (1) was recently disclosed and patented by Pfizer for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has received fast-track status from the USA Food and Drug Administration (FDA) and has entered phase III clinical trials as a possible replacement for Paxlovid. Like nirmatrelvir (2) in Paxlovid, this orally active drug candidate is designed to target viral main proteases (Mpro) through reversible covalent interaction of its nitrile warhead with the active site thiol of the chymotrypsin-like cysteine protease (3CL protease). Inhibition of Mpro hinders the processing of the proteins essential for viral replication in vivo. However, ibuzatrelvir apparently does not require ritonavir (3), which is coadministered in Paxlovid to block human oxidative metabolism of nirmatrelvir. Here, we report the crystal structure of the complex of ibuzatrelvir with the active site of SARS-CoV-2 Mpro at 2.0 Å resolution. In addition, we show that ibuzatrelvir also potently inhibits the Mpro of Middle East respiratory syndrome-related coronavirus (MERS-CoV), which is fortunately not widespread but can be dangerously lethal (∼36% mortality). Co-crystal structures show that the binding mode of the drug to both active sites is similar and that the trifluoromethyl group of the inhibitor fits precisely into a critical S2 substrate binding pocket of the main proteases. However, our results also provide a rationale for the differences in potency of ibuzatrelvir for these two proteases due to minor differences in the substrate preferences leading to a weaker H-bond network in MERS-CoV Mpro. In addition, we examined the reversibility of compound binding to both proteases, which is an important parameter in reducing off-target effects as well as the potential immunogenicity. The crystal structures of the ibuzatrelvir complexes with Mpro of SARS-CoV-2 and of MERS-CoV will further assist drug design for coronaviral infections in humans and animals.
General Boc-Deprotection and Coupling Procedure
This procedure was based on a literature procedure.1
The Boc-protected building block (1.0
equiv) was dissolved in 50/50 TFA/DCM and stirred for 1 h at room temperature. The reaction
mixture was then concentrated in vacuo and co-evaporated with DCM (5 × 5 mL). In a separate
RBF the carboxylic acid building block (1.0 equiv) and HATU (1.0 equiv) were dissolved in
DMF. HOAt (0.6 M in DMF) (0.1 equiv) and DIPEA (3.0 equiv) were added and the reaction
mixture was left to incubate at room temperature for 10 mins, as it turned yellow. The previously
concentrated Boc-deprotected building block was dissolved in DMF and added dropwise to the
incubating solution. The reaction mixture was capped under a blanket of argon and stirred at room
temperature for 2–3 h. The reaction mixture was diluted with 5 mL each of water and ethyl acetate
and the layers separated. The aqueous layer was extracted further with ethyl acetate (3 × 5 mL),
and all ethyl acetate layers combined and washed with sat. aq. NaHCO3 (10 mL), 1 M HCl (10
mL), water (2 × 10 mL) and brine (10 mL). It was then dried over Na2SO4, filtered, and
concentrated in vacuo to furnish the product.
Methyl ((S)-1-((2S,4R)-2-(((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)carbamoyl)-4-
(trifluoromethyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (1) Ibuzatrelvir
This known compound was synthesized according to the General Boc-Deprotection and
Coupling Procedure with building blocks 7 and 8. The characterization data matches the literature
report (IPN: WO2021250648A1). The crude material was obtained as a dark yellow sticky residue
that was then purified with flash column chromatography with an eluent of 92:8 EtOAc:MeOH.
The desired compound had an Rf
= 0.40 and was visible with KMnO4 stain. After concentration
of desired fractions, 1 was isolated as a clear, colorless oil that solidified to a white solid (0.051 g,
53%) This compound was isolated and used for all experiments as a mixture of diastereomers in a
ratio of about 2:1 and rotamers present, with only the major set of resonances reported, which are
for the desired isomer. It can be separated using high performance liquid chromatography (HPLC)
methods, as listed in the HPLC Separation of Ibuzatrelvir Diastereomers section.
IR (DCM cast film, vmax / cm–1) 3292, 3053, 2959, 2909, 2875, 1695, 1643, 1550, 1443, 1401,
1370, 1332, 1270, 1236, 1200, 1164, 1130
1H NMR (500 MHz, CDCl3) δH 8.32 (1H, d, J = 7.6 Hz), 6.22 (1H, br), 5.74 (1H, d, J = 9.3 Hz),
4.96 – 4.87 (1H, m), 4.54 (1H, dd, J = 8.6, 3.6 Hz), 4.30 (1H, d J = 9.9 Hz), 3.99 – 3.88 (2H, m),
3.65 (3H, s), 3.42 – 3.26 (2H, m), 2.66 – 2.57 (1H, m), 2.52 – 2.43 (1H, m), 2.40 – 2.28 (3H, m),
1.97 – 1.88 (1H, m), 1.84 – 1.75 (2H, m), 0.99 (9H, s)
13C {1H} NMR (125 MHz, CDCl3) δC 179.1, 171.4, 171.1, 156.9, 126.1 (q, J = 276.3 Hz), 118.3,
59.4, 58.9, 52.4, 47.3, 42.4 (q, J = 29.5 Hz), 40.4, 39.1 37.5, 35.6, 34.2, 28.2, 28.0, 26.3
SR: [α]D
26 = –35.71 (c = 0.21, DCM)
HRMS: (ESI) Calcd for C21H30F3N5NaO5 [M + Na]+
512.2091, found 512.2088
References
- ^ Allerton CM, Arcari JT, Aschenbrenner LM, Avery M, Bechle BM, Behzadi MA, et al. (August 2024). “A Second-Generation Oral SARS-CoV-2 Main Protease Inhibitor Clinical Candidate for the Treatment of COVID-19”. Journal of Medicinal Chemistry. 67 (16): 13550–13571. doi:10.1021/acs.jmedchem.3c02469. PMC 11345836. PMID 38687966.
- ^ Chen P, Van Oers TJ, Arutyunova E, Fischer C, Wang C, Lamer T, et al. (August 2024). “A Structural Comparison of Oral SARS-CoV-2 Drug Candidate Ibuzatrelvir Complexed with the Main Protease (Mpro) of SARS-CoV-2 and MERS-CoV”. JACS Au. 4 (8): 3217–3227. doi:10.1021/jacsau.4c00508. PMC 11350714. PMID 39211604.
- ^ Jump up to:a b Brewitz L, Schofield CJ (July 2024). “Fixing the Achilles Heel of Pfizer’s Paxlovid for COVID-19 Treatment”. Journal of Medicinal Chemistry. 67 (14): 11656–11661. doi:10.1021/acs.jmedchem.4c01342. PMC 11284777. PMID 38967233.
| Clinical data | |
|---|---|
| Other names | PF-07817883 |
| Routes of administration | Oral |
| Legal status | |
| Legal status | Investigational |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 2755812-39-4 |
| PubChem CID | 163362000 |
| DrugBank | 111 |
| ChemSpider | 128942571 |
| UNII | KZ2X7QH2VT |
| Chemical and physical data | |
| Formula | C21H30F3N5O5 |
| Molar mass | 489.496 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
- [1]. Owen, et al. Preparation of peptidomimetic nitriles as SARS-CoV-2 3CL protease inhibitors and methods for the treatment of COVID-19. World Intellectual Property Organization, WO2021250648 A1. 2021-12-16.[2]. Mahta Mortezavi, et al. Virologic Response and Safety After Oral Administration of Ibuzatrelvir, a Novel SARS-CoV-2 Mpro Inhibitor, in Non-Hospitalized Adults With Symptomatic COVID-19. European Congress of Clinical Microbiology and Infectious Disease (ECCMID) 2024; 2024 April 27-30.[3]. Westberg M, et al. An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations[J]. Sci Transl Med. 2024 Mar 13;16(738):eadi0979.[4]. Allerton CMN, et al. A Second-Generation Oral SARS-CoV-2 Main Protease Inhibitor Clinical Candidate for the Treatment of COVID-19[J]. J Med Chem. 2024 Apr 30. [Content Brief]
////Ibuzatrelvir, PF 07817883, PF-07817883, PF07817883, KZ2X7QH2VT