Ensitrelvir

S-217622, S 217622, Xocova, SHIONOGI,

6-[(6-chloro-2-methylindazol-5-yl)amino]-3-[(1-methyl-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione

CAS 2647530-73-0

C22H17ClF3N9O2531.9
Synonyms	BDBM513874bioRxiv20220126.477782, S-217622

Ensitrelvir fumarate
CAS No. : 2757470-18-9

C₂₂ H₁₇ Cl F₃ N₉ O₂ . C₄ H₄ O₄

1,3,5-Triazine-2,4(1H,3H)-dione, 6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]dihydro-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-, (6E)-, (2E)-2-butenedioate (1:1)

Formula:	C26H21ClF3N9O6
M. Wt. :	647.95

A Phase 1 study of S-217622 in healthy adult participants (jRCT2031210202)

Japan Registry of Clinical Trials Web Site 2021, July 16

PMDA APPROVED 2022/11/22, Xocova

Ensitrelvir^[1] (code name S-217622, brand name Xocova)^[2] is an antiviral drug developed by Shionogi in partnership with Hokkaido University, which acts as an orally active 3C-like protease inhibitor for the treatment of COVID-19 infection.^[3][4] It is taken by mouth, and has been successfully tested against the recently emerged Omicron variant.^[5]

About S-217622

S-217622, a therapeutic drug for COVID-19, is a 3CL protease inhibitor created through joint research between Hokkaido University and Shionogi. SARS-CoV-2 has an enzyme called 3CL protease, which is essential for the replication of the virus. S-217622 suppresses the replication of SARS-CoV-2 by selectively inhibiting 3CL protease. Shionogi has already been submitting the non-clinical, manufacturing/CMC data, and clinical trial data obtained so far to the PMDA. Currently the Phase 3 part of a Phase 2/3 clinical trial in patients with mild/moderate symptoms and the Phase 2b/3 part in patients with asymptomatic/only mild symptoms are in progress.

SYN

Discovery of S-217622, a Non-Covalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19

 View ORCID ProfileYuto Unoh,  View ORCID ProfileShota Uehara,  View ORCID ProfileKenji Nakahara,  View ORCID ProfileHaruaki Nobori, Yukiko Yamatsu,  View ORCID ProfileShiho Yamamoto,  View ORCID ProfileYuki Maruyama,  View ORCID ProfileYoshiyuki Taoda,  View ORCID ProfileKoji Kasamatsu,  View ORCID ProfileTakahiro Suto, Kensuke Kouki,  View ORCID ProfileAtsufumi Nakahashi, Sho Kawashima,  View ORCID ProfileTakao Sanaki, Shinsuke Toba, Kentaro Uemura, Tohru Mizutare,  View ORCID ProfileShigeru Ando,  View ORCID ProfileMichihito Sasaki,  View ORCID ProfileYasuko Orba,  View ORCID ProfileHirofumi Sawa,  View ORCID ProfileAkihiko Sato,  View ORCID ProfileTakafumi Sato,  View ORCID ProfileTeruhisa Kato,  View ORCID ProfileYuki Tachibana

doi: https://doi.org/10.1101/2022.01.26.477782

https://www.biorxiv.org/content/10.1101/2022.01.26.477782v1.full

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and threatens public health and safety. Despite the rapid global spread of COVID-19 vaccines, effective oral antiviral drugs are urgently needed. Here, we describe the discovery of S-217622, the first oral non-covalent, non-peptidic SARS-CoV-2 3CL protease inhibitor clinical candidate. S-217622 was discovered via virtual screening followed by biological screening of an in-house compound library, and optimization of the hit compound using a structure-based drug-design strategy. S-217622 exhibited antiviral activity in vitro against current outbreaking SARS-CoV-2 variants and showed favorable pharmacokinetic profiles in vivo for once-daily oral dosing. Furthermore, S-217622 dose-dependently inhibited intrapulmonary replication of SARS-CoV-2 in mice, indicating that this novel non-covalent inhibitor could be a potential oral agent for treating COVID-19.

Chemistry

The synthetic scheme for compound 1 is described in Scheme 1. Starting from the pyrazole derivative 4, cyclization with Ethyl isocyanatoacetate and CDI was conducted, giving 5 in 90% yield. Then, an alkylation with 5-bromomethyl-1,2,3-trifluorobenzene followed by introduction of a 4-difluoromethoxy-2-methylaniline unit, to give 7 (40% in 2 steps). The ester group in 7 was hydrolyzed and then amidated with methylamine, yielding 1 (58% in 2 steps). Compound 2 was synthesized similarly as shown in Scheme 2.

S-217622 (3) was synthesized as described in Scheme 3. Starting from known compound 9,²¹ an alkylation with 1-(bromomethyl)-2,4,5-trifluorobenzene gave 10 in 93% yield. Then, the 3-tert-Bu group was removed and the triazole unit was introduced, and the substitution of the SEt moiety with the indazole unit finally gave S-217622 (3).

21 Kai, H.; Kameyama, T.; Horiguchi, T.; Asahi, K.; Endoh, T.; Fujii, Y.; Shintani, T.; Nakamura, K.; Matsumoto, S.; Hasegawa, T.; Oohara, M.; Tada, Y.; Maki, T.; Iida, A. Preparation of triazine derivatives and pharmaceutical compound that contains same and exhibits analgesic activity. WO 2012020749 A1, Feb 16, 2012

Scheme 1.

Reagents and Conditions: (a) ethyl isocyanato-acetate, DBU, CDI, DMA, –10 °C to rt, 90%; (b) 5-bromomethyl-1,2,3-trifluorobenzene, N,N-diisopropylethylamine, DMA, 60 °C; (c) 4-difluoromethoxy-2-methylaniline, tert-butanol, 100 °C, 40% in 2 steps; (d) (i) NaOH aq., THF/MeOH, rt; (ii) methylamine, HATU, N,N-diisopropylethylamine, THF, rt., 58% in 2 steps.

Scheme 2.

Reagents and Conditions: (a) 6-chloro-2-methyl-2H-indazol-5-amine, tert-amyl alcohol, 100 °C, 44% in 2 steps from 5; (b) (i) NaOH aq., THF/MeOH, rt; (ii) methylamine, HATU, N,N-diisopropylethylamine, THF, rt., 29% in 2 steps.

Scheme 3.

Reagents and Conditions: (a) 1-(bromomethyl)-2,4,5-trifluorobenzene, K₂CO₃, MeCN, 80 °C, 93%; (b) TFA, rt, 97%; (c) 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride, K₂CO₃, DMF, 60 °C, 45%; (d) 6-chloro-2-methyl-2H-indazol-5-amine, LHMDS, THF, 0 °C to rt., 25%.

(6E)-6-[(6-Chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-(2,4,5-trifluorobenzyl)-1,3,5-triazinane-2,4-dione (3, S-217622)

To a solution of 12 (300 mg, 0.727 mmol) and 6-chloro-2-methyl-2H-indazol-5-amine (172 mg, 0.946 mmol) in THF (6 mL) was added LHMDS (1M in THF; 1.46 mL, 1.46 mmol) dropwisely at 0 °C. The reaction mixture was stirred at 0 °C for 2.5 h and then at rt for 40 min. The reaction was quenched with aqueous NH₄Cl solution, and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl₃/MeOH gradient, 0-20% MeOH). The solid was recrystallized from acetone/H₂O to afford 3 (S-217622) (95.3 mg, 25%) as a pale brown solid. ¹H NMR (400 MHz, DMSO-d₆, DCl in D₂O) δ 3.90 (3H, s), 4.15 (3H, s), 5.04 (2H, s), 5.26 (2H, s), 7.44 (1H, m), 7.52-7.65 (2H, m), 7.73 (1H, s), 8.40 (1H, s), 9.31 (1H, s). ¹³C NMR (100 MHz, DMSO-d₆, DCl in D₂O) δ 37.34, 38.04, 40.06, 40.29, 106.16 (dd, J = 28.2, 21.6 Hz), 116.46-116.70, 116.70, 120.54-120.76, 120.76, 125.93, 129.10, 132.35, 143.84, 145.98, 146.38 (ddd, J = 241.4, 12.5, 3.7 Hz), 146.60, 148.52 (td, J = 247.7, 13.6 Hz), 150.43, 150.50, 155.22 (ddd, J = 244.3, 10.3, 2.2 Hz), 155.58. HRMS-ESI (m/z): [M + H]⁺ calcd for [C₂₂H₁₈ F₃ClN₉O₂]⁺ 532.1219; found 532.1221.

Preparation of Compound 3 (S-217622) fumaric acid co-crystal

A mixture of 3 (S-217622) (1.17 g, 2.2 mmol) and fumaric acid (278 mg, 2.4 mmol) in EtOAc (5.9 mL) was stirred at room temperature for 45 min. The suspension was filtrated to afford 3 (S-217622) fumaric acid co-crystal (1.37 g, 95 %) as a white solid. ¹H NMR (400 MHz, pyridine-d₅) δ 3.64 (s, 3H), 3.99 (s, 3H), 5.56 (s, 2H), 5.61 (s, 2H), 7.16-7.25 (m, 2H), 7.44 (s, 2H), 7.81 (s, 1H), 7.89 (s, 1H), 7.89-7.97 (m, 1H), 8.32 (s, 1H).

Notes

SHIONOGI has applied for a patent covering 1, 2, and 3 (S-217622). Y.U., S.U., K.N., H.N., Y.Y., S.Y., Y.M., Y.T., K.K., T.S., K.K., A.N., S.K., T.S., S.T., K.U., T.M., S.A., A.S., T.S., T.K., and Y.T. are employees of SHIONOGI & Co., Ltd. S.U., K.N., H.N., Y.M., Y.T., K.K., T.S., K.K., S.K., TS, S.T., K.U., T.S., and T.K. are shareholders in SHIONOGI & Co., Ltd. M.S., Y.O., and H.S. are financially supported by the joint research fund from SHIONOGI & Co., Ltd.

• Supporting information[supplements/477782_file02.pdf]

see spectrum at end of page

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Oral antiviral medications, in addition to vaccines, are expected to play an important role in treating coronavirus disease 2019 (COVID-19), which is caused by infection with the severe acute respiratory disease coronavirus-2 (SARS-CoV-2).

These drugs must have significant antiviral activity, as well as target specificity, oral bioavailability, and metabolic stability. Although several antiviral compounds have been reported as possible SARS-CoV-2 inhibitors in vitro, only a few of these drugs have been shown to be effective in vivo.

Ensitrelvir, a novel SARS-CoV-2 antiviral

Ensitrelvir (code name S-217622, brand name Xocova),  is a new inhibitor of the SARS-CoV-2 major protease (Mpro), also known as 3C-like protease, has been shown to reduce the viral load and help alleviate the severity of SARS-CoV-2 in infected hamsters. In cells, low nanomolar to sub-micromolar doses of S-217622 suppress viral growth. In hamsters, oral treatment of S-217622 showed excellent pharmacokinetic qualities and hastened recovery from acute SARS-CoV-2 infection.

S-217622 also demonstrated antiviral effectiveness against SARS-CoV-2 variants of concern (VOCs), such as the highly pathogenic Delta variant and the newly discovered Omicron variant. Overall, these findings show that S-217622, which is an antiviral drug that is currently being tested in Phase II/III clinical trials, has impressive antiviral efficiency and effectiveness against SARS-CoV-2 and could be a viable oral treatment option for COVID-19.

History

It has reached Phase III clinical trials.^[3] The Japanese government is reportedly considering allowing Shionogi permission to apply for approval for medical use before the final steps of trials are completed, potentially speeding up the release for sale. This conditional early approval system has previously been used in Japan to accelerate the progression to market of other antiviral drugs targeting COVID-19, including remdesivir and molnupiravir.^[6] In a study of 428 patients, viral load was reduced, but symptoms were not significantly reduced. ^[7]

It became the first Japanese domestic pill to treat COVID-19, third to be regulatorally approved in Japan; in February 2022.^[8]

References

1. ^ World Health Organization (2021). “International Nonproprietary Names for Pharmaceutical Substances. Proposed INN: List 126” (PDF). WHO Drug Information. 35 (4): 1135.
2. ^ Xocova: Powerful New Japanese Pill for Coronavirus Treatment. BioPharma Media, February 2022
3. ^ Jump up to:^a b Unoh Y, Uehara S, Nakahara K, Nobori H, Yamatsu Y, Yamamoto S, et al. (January 2022). “Discovery of S-217622, a Non-Covalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19”. bioRxiv. doi:10.1101/2022.01.26.477782. S2CID 246367525.
4. ^ “Shionogi presents positive Ph II/III results for COVID-19 antiviral S-217622”. thepharmaletter.com. 31 January 2022.
5. ^ Shionogi’s new COVID pill appears to ease omicron symptoms. Nikkei Asia, 21 December 2021
6. ^ Japan to consider early approval for Shionogi COVID-19 pill. Japan Times, 8 February 2022
7. ^ https://www.reuters.com/business/healthcare-pharmaceuticals/japans-shionogi-seeks-approval-oral-covid-19-drug-2022-02-25/^{[bare URL]}
8. ^ “Japan’s Shionogi seeks approval for COVID-19 pill”. Reuters. Reuters. 25 February 2022.

Clinical data
Other names	S-217622
Identifiers
showIUPAC name
PubChem CID	162533924
Chemical and physical data
Formula	C22H17ClF3N9O2
Molar mass	531.88 g·mol−1
3D model (JSmol)	Interactive image
showSMILES
showInChI

Journal reference:

• Sasaki, M., Tabata, K., Kishimoto, M., et al. (2022). Oral administration of S-217622, a SARS-CoV-2 main protease inhibitor, decreases the viral load and accelerates recovery from clinical aspects of COVID-19. bioRxiv. doi:10.1101/2022.02.14.480338. https://www.biorxiv.org/content/10.1101/2022.02.14.480338v1.full.

///////////Ensitrelvir, S-217622, S 217622, Xocova, SHIONOGI, CORONA VIRUS, covid 19