{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T22:51:56Z","timestamp":1767912716611,"version":"3.49.0"},"reference-count":31,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T00:00:00Z","timestamp":1690243200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Education Department of Liaoning Province, China","award":["LJKZ0804"],"award-info":[{"award-number":["LJKZ0804"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>SARS-CoV-2 is a highly contagious and pathogenic virus that first appeared in late December 2019 and caused a global pandemic in a short period. The virus is a single-stranded RNA virus belonging to the Coronaviridae family. Numerous treatments have been developed and tested in response to the pandemic, particularly antiviral drugs. Among them, GS441524 (GS441), a nucleoside antiviral drug, has demonstrated promising results in inhibiting SARS-CoV-2. Nevertheless, the limited oral bioavailability of GS441 restricts its application to patients with the virus. In this study, a novel prodrug of GS441 (NGP-1) with an isobutyl ester and cyclic carbonate structure was designed and synthesized. Its purity and the stability in different artificial digestive juices of NGP-1 was determined with HPLC-DAD methods. The pharmacokinetics of NGP-1 and GS441 were studied in rats via gavage administration. A new LC-MS\/MS method was developed to quantitatively analyze GS441 in plasma samples. The results showed that the ka, Cmax, and MRT of converted GS441 from NGP-1 were 5.9, 3, and 2.5 times greater than those of GS441 alone. The Frel of NGP-1 was approximately four-fold that of GS441, with an AUC0\u2013\u221e of 9716.3 h\u00b7ng mL\u22121. As a prodrug of GS441, NGP-1 increased its lipophilicity, absorption, and bioavailability, indicating that it holds promise in improving the clinical efficacy of anti-SARS-CoV-2 medications.<\/jats:p>","DOI":"10.3390\/molecules28155634","type":"journal-article","created":{"date-parts":[[2023,7,26]],"date-time":"2023-07-26T01:09:01Z","timestamp":1690333741000},"page":"5634","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Assessment of Purity, Stability, and Pharmacokinetics of NGP-1, a Novel Prodrug of GS441254 with Potential Anti-SARS-CoV-2 Activity, Using Liquid Chromatography"],"prefix":"10.3390","volume":"28","author":[{"given":"Chen","family":"Sun","sequence":"first","affiliation":[{"name":"School of Pharmacy, Jinzhou Medical University, Jinzhou 121001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jinzhou Medical University, Jinzhou 121001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fengzhi","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jinzhou Medical University, Jinzhou 121001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qianqian","family":"Zheng","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jinzhou Medical University, Jinzhou 121001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunmei","family":"Dai","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jinzhou Medical University, Jinzhou 121001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Wei","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jinzhou Medical University, Jinzhou 121001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guochao","family":"Liao","sequence":"additional","affiliation":[{"name":"International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuqi","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jinzhou Medical University, Jinzhou 121001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"858","DOI":"10.3892\/mmr.2021.12498","article-title":"Current treatment strategies for COVID-19 (Review)","volume":"24","author":"Han","year":"2021","journal-title":"Mol. Med. Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1111\/joim.13478","article-title":"Advances in the Omicron variant development","volume":"292","author":"Vitiello","year":"2022","journal-title":"J. Intern. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"100794","DOI":"10.1016\/j.drup.2021.100794","article-title":"An update on drugs with therapeutic potential for SARS-CoV-2 (COVID-19) treatment","volume":"59","author":"Rosik","year":"2021","journal-title":"Drug Resist. Updates"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1080\/07853890.2022.2031274","article-title":"Emerging COVID-19 variants and their impact on SARS-CoV-2 diagnosis, therapeutics and vaccines","volume":"54","author":"Fernandes","year":"2022","journal-title":"Ann. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Winger, A., and Caspari, T. (2021). The spike of concern-the novel variants of SARS-CoV-2. Viruses, 13.","DOI":"10.3390\/v13061002"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2909","DOI":"10.2174\/1568026621666210728094019","article-title":"Advancement of prodrug approaches for nucleotide antiviral agents","volume":"21","author":"Li","year":"2021","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"100128","DOI":"10.1016\/j.onehlt.2020.100128","article-title":"Current knowledge about the antivirals remdesivir (GS-5734) and GS-441524 as therapeutic options for coronaviruses","volume":"9","author":"Amirian","year":"2020","journal-title":"One Health"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2977","DOI":"10.1093\/jac\/dkaa239","article-title":"Pharmacokinetics of in two critically ill patients who recovered from COVID-19","volume":"75","author":"Tempestilli","year":"2020","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e00945","DOI":"10.1002\/prp2.945","article-title":"Nucleoside analog GS-441524: Pharmacokinetics in different species, safety, and potential effectiveness against COVID-19","volume":"10","author":"Rasmussen","year":"2022","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"461","DOI":"10.2174\/1389200033489253","article-title":"Design of ester prodrugs to enhance oral absorption of poorly permeable compounds: Challenges to the discovery scientist","volume":"4","author":"Beaumont","year":"2003","journal-title":"Curr. Drug Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e0022222","DOI":"10.1128\/aac.00222-22","article-title":"Remdesivir and GS-441524 Retain Antiviral Activity against Delta, Omicron, and Other Emergent SARS-CoV-2 Variants","volume":"66","author":"Pitts","year":"2022","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1772","DOI":"10.1093\/jac\/dkaa152","article-title":"Development and validation of a UHPLC-MS\/MS method for quantification of the prodrug remdesivir and its metabolite GS-441524: A tool for clinical pharmacokinetics of SARS-CoV-2\/COVID-19 and Ebola virus disease","volume":"75","author":"Avataneo","year":"2020","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6771","DOI":"10.1073\/pnas.1922083117","article-title":"Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection","volume":"117","author":"Feldmann","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e0115521","DOI":"10.1128\/AAC.01155-21","article-title":"Rethinking remdesivir: Synthesis, antiviral activity, and pharmacokinetics of oral lipid prodrugs","volume":"65","author":"Schooley","year":"2021","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"43395","DOI":"10.1038\/srep43395","article-title":"GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses","volume":"7","author":"Lo","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e13105","DOI":"10.15252\/emmm.202013105","article-title":"A comparative analysis of remdesivir and other repurposed antivirals against SARS-CoV-2","volume":"13","author":"Simonis","year":"2021","journal-title":"EMBO Mol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"69","DOI":"10.5582\/bst.2020.01020","article-title":"Drug treatment options for the 2019-new coronavirus (2019-nCoV)","volume":"14","author":"Lu","year":"2020","journal-title":"Biosci. Trends"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1002\/jps.20542","article-title":"Enzymes involved in the bioconversion of ester-based prodrugs","volume":"95","author":"Liederer","year":"2006","journal-title":"J. Pharm. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3857","DOI":"10.1021\/jo049971d","article-title":"Enantioselective total synthesis of (+)-brefeldin A and 7-epi-brefeldin A","volume":"69","author":"Wu","year":"2004","journal-title":"J. Org. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1021\/jacs.7b11824","article-title":"Reworkable polyhydroxyurethane films with reversible acetal networks obtained from multifunctional six-membered cyclic carbonates","volume":"140","author":"Matsukizono","year":"2018","journal-title":"J. Am. Chem. Soc."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.ejmech.2012.12.006","article-title":"Synthesis of novel naphthoquinone aliphatic amides and esters and their anticancer evaluation","volume":"60","author":"Kongkathip","year":"2013","journal-title":"Eur. J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"70","DOI":"10.2174\/187231209788654081","article-title":"Esterase activities in the blood, liver and intestine of several preclinical species and humans","volume":"3","author":"Berry","year":"2009","journal-title":"Drug Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e4850","DOI":"10.1002\/bmc.4850","article-title":"Novel HPTLC densitometric methods for determination of tamsulosin HCl and tadalafil in their newly formulated dosage form: Comparative study and green profile assessment","volume":"34","author":"Tantawy","year":"2020","journal-title":"Biomed. Chromatogr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1093\/chromsci\/48.8.624","article-title":"Selective determination of ertapenem and imipenem in the presence of their degradants","volume":"48","author":"Elragehy","year":"2010","journal-title":"J. Chromatogr. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Rasmussen, H.B., J\u00fcrgens, G., Thomsen, R., Taboureau, O., Zeth, K., Hansen, P.E., and Hansen, P.R. (2021). Cellular Uptake and Intracellular Phosphorylation of GS-441524: Implications for its effectiveness against COVID-19. Viruses, 13.","DOI":"10.3390\/v13071369"},{"key":"ref_26","first-page":"235","article-title":"Recent advances in prodrugs and antedrugs","volume":"1","author":"Lee","year":"1998","journal-title":"Curr. Opin. Drug Discov. Devel."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1002\/ddr.21468","article-title":"Microbial esterases and ester prodrugs: An unlikely marriage for combating antibiotic resistance","volume":"80","author":"Larsen","year":"2019","journal-title":"Drug Dev. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1007\/s00204-023-03467-7","article-title":"Toxicology of 3-monochloropropane-1,2-diol and its esters: A narrative review","volume":"97","author":"Fattore","year":"2023","journal-title":"Arch. Toxicol."},{"key":"ref_29","unstructured":"Li, W., Hao, L., Li, P., and Zhou, P. (2022). The Synthesis and Application of Nucleoside Compounds with Cyclic Carbonate Ester. (CN 114437159B)."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e4347","DOI":"10.1002\/bmc.4347","article-title":"Novel determination of sofosbuvir and velpatasvir in human plasma by UPLC-MS\/MS method: Application to a bioequivalence study","volume":"32","author":"Rezk","year":"2018","journal-title":"Biomed. Chromatogr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e5459","DOI":"10.1002\/bmc.5459","article-title":"Pharmacokinetic study of deufruquintinibs in rats by HPLC-MS\/MS after oral administration","volume":"36","author":"Hu","year":"2022","journal-title":"Biomed. Chromatogr."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/15\/5634\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:18:46Z","timestamp":1760127526000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/15\/5634"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,25]]},"references-count":31,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["molecules28155634"],"URL":"https:\/\/doi.org\/10.3390\/molecules28155634","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,25]]}}}