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Adenosine Analogue VV116

The nucleoside analogue VV116 (1, Fig. 1) is a nucleoside analogue derived from remdesivir (2) showing antiviral activity against SARS-CoV-2 first described by Leike Zhang, H. Eric Xu, Jingshan Shen and co-workers from the Shanghai Institute of Materia Medica and the University of Chinese Academy of Science Beijing. In their initial report published in a letter to Cell Research[1] and an article in Bioorganic & Medicinal Chemistry[2] they claimed a higher bioavailability for compound 1 compared to 2 which had to be intravenously administered. The synthesis of remdesivir (2) can be found here.

vv116.png

Figure 1: Structure of VV116 (1) and remdesivir (2).

Synthesis of VV116

The nucleoside analogue can be synthesized in several steps from ribose (3) as shown in Scheme 1 and 2. However, some intermediates like 5 may be commercially available. Jeroen Codée described in 2014[3] the synthesis of protected ribose 4 in 3 steps, then Albright-Goldman oxidation gave access to ester 5 [4] as shown in Scheme 1. The following steps were first described by Thomas Chilar and Sina Bavari in Nature 2016.[5] Activation of iodine 6 allowed the addition to 5 yielding 7 in poor yield. Finally, activation of the alcohol was followed by the substitution with the cyanide in a diastereoselective fashion to 8; a common precursor for remdesivir (2) and VV116 (1).

vv116-2.png

Scheme 1: Synthesis of the common precursor 8 towards antiviral VV116 (1).

With 8 in hand, Jingshan Shen and co-workers reported the synthesis of VV116 (1) as shown in Scheme 2. Iodination allowed the activation of the purine analogue in the C-7 position. This was followed by the palladium-catalyzed deuterium introduction to 10. Then, Lewis-acidic deprotection gave 11. Before the ester formation, the primary amine has to be protected and therefore 12 was synthesized. Now, common coupling conditions gave the triester and subsequent deprotection liberated 13 in good yield. Finally, 13 was converted into the HBr salt 1.

vv116-3.png

Scheme 2: Finalization of the synthesis of VV116 (1).

Antiviral Activity against SARS-CoV-2

Initial SAR studies

As reported by Jingshan Shen and co-workers, several remdesivir analogues were tested for their antiviral activity. Remdesivir (2) is considered to be a ProTide type pro drug, but also parent compound 16a is showing antiviral activity. This compound was the starting point for the conducted SAR studies using cellular assays.[1][2] However, most of them render inactive. In detail, modifications of the base like in 15 mostly produced inactive compounds. Fluorine 15a showed moderate activity, whereas deuterated 15c retained the activity of 16a. The removal of C1'-CN led to 16b a highly cytotoxic compound. Modification of C2' or C3' again mostly showed no activity (e.g. 17). In the end, deuterated compound 15c was carried forward for further modifications. It should be noted that the difference in activity between the deuterated and the non-deuterated compound (16a vs 15c) is neglectable.

vv116-4.png

compound
antiviral assessment
EC50
CC50
VV116 (1) highly active 0.35 µM
280 µM
15a (X = F)
moderate activity
3.30 µM
n.d.
15b (X = Br, Cl, I, OH, CN)
no activity
n.d.
n.d.
15c (X = D)
highly active
0.39 µM
> 500 µM
16a
reference compound
0.59 µM > 500 µM
16b
high cytotoxicity
n.d.
n.d.
17
no activity
n.d.
n.d.

Table 1: Initial SAR study towards VV116 (1). Antiviral activity against SARS-CoV-2 and cytotoxicity in Vero E6 cells.

Then different esterification patterns were probed. As ester moieties often get cleaved after admission, their main purpose is to change their solubility and cell permeability properties. Therefore, esterification of 15c led to several nucleoside analogues with similar antiviral activity (see activity 1 vs 15c), however, with changed bioavailability. In the end, VV116 (1) showed the best properties concerning bioavailability (F = 80%; in comparison to 15c F = 22%).[1]

Phase 3 Trial (R. Zhao, 2022)

Ren Zhao and colleagues from the Shanghai Jiao Tong University (Shanghai, China) reported phase 3 results in the New England Journal of Medicine in late 2022.[6] Their study had a total of 822 patients during a local SARS-CoV-2 outbreak in early 2022 (omicron), around half of them receiving VV116 (1) whereas the other half received Nirmatrelvir–Ritonavir (paxlovid) as a treatment. Their results indicated, that the treatment with 1 was not inferior to paxlovid and no patient in both group had progressed to severe conditions. Furthermore, patients receiving 1 reported fewer adverse events compared to paxlovid.

Antiviral Activity against RSV

In 2022, Yuanchao Xie, Leike Zhang and co-workers reported the antiviral activity of VV116 (1) against respiratory syncytial virus (RSV) in the journal Signal Transduction and Targeted Therapy.[7] The study revealed a high activity of VV116 (1), however, remdesivir (2) showed a 50-fold higher activity and at the same time lower cytotoxicity (see Table 2). Next, in vivo testing revealed that a medium dose of VV116 (1) (50 mg/kg) already was sufficient for decreasing the virus under the detection limit in lung tissue 4d after infection in mice.  Pharmacokinetic studies showed, that VV116 (1) was readily metabolized to active analogue 15c, which itself had a short elimination half-time (2.3-4.5 h).

compound
EC50
CC50
VV116 (1) 1.01 µM
95.8 µM
16a
0.82 µM > 500 µM
15c (X = D)
1.59 µM
> 500 µM
Remdesivir (2) 0.02 µM 226 µM

Table 2: Activity against RSV A2 and cytotoxicity in A549 cells.

Literature

[1] Y. Xie, W. Yin, Y. Zhang, et al. Design and development of an oral remdesivir derivative VV116 against SARS-CoV-2. Cell Res 2021, 31, 1212–1214. https://doi.org/10.1038/s41422-021-00570-1

[2] D. Wei, T. Hu, Y. Zhang, W. Zheng, H. Xue, J. Shen, Y. Xie, H. A. Aisa. Potency and pharmacokinetics of GS-441524 derivatives against SARS-CoV-2, Bioorg Med Chem 2021, 46, 116364. https://doi.org/10.1016/j.bmc.2021.116364

[3] E.R. van Rijssel, P. van Delft, G. Lodder, H.S. Overkleeft, G.A. van der Marel, D.V. Filippov, J. D. C. Codée Furanosyl Oxocarbenium Ion Stability and Stereoselectivity Angew Chem Int Ed 2014, 53, 39, 10381-10385. https://doi.org/10.1002/anie.201405477

[4]  J. Bouton, S. Van Calenbergh, J. Hullaert Sydnone Ribosides as a Platform for the Synthesis of Pyrazole C-Nucleosides: A Unified Synthesis of Formycin B and Pyrazofurin Org Lett 2020, 22, 23, 9287-9291. https://doi.org/10.1021/acs.orglett.0c03523

[5] T. Warren, R. Jordan, M. Lo, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 2016, 531, 381–385. https://doi.org/10.1038/nature17180

[6] Z. Cao, W. Gao, H. Bao, et al. VV116 versus Nirmatrelvir–Ritonavir for Oral Treatment of Covid-19 New Engl J Med 2022. https://doi.org/10.1056/NEJMoa2208822

[7] R. Zhang, Y. Zhang, W. Zheng, W. et al. Oral remdesivir derivative VV116 is a potent inhibitor of respiratory syncytial virus with efficacy in mouse model. Sig Transduct Target Ther 2022, 7, 123. https://doi.org/10.1038/s41392-022-00963-7