Recent advances in drug substance development – prodrug strategies for enhancing the bioavailability and potency of antiviral nucleosides

Andrzej Kutner

doi:10.20883/medical.e878

Authors

Andrzej Kutner Department of Drug Chemistry, Faculty of Pharmacy, The Medical University of Warsaw, Warsaw, Poland https://orcid.org/0000-0002-9518-4142

DOI:

https://doi.org/10.20883/medical.e878

Keywords:

drug substance development, bioavailability, dissolution, prodrug strategy, phosphoramidate optimization

Abstract

Bioavailability is a prerequisite for drug activity. In vivo bioavailability (intestinal permeability), linked to drug substance solubility and drug product dissolution, became the basis of Gordon L. Amidon’s Biopharmaceutical Classification System. One method of improving the drug substance’s bioavailability is to modify its structure chemically, leading to increased lipophilicity and the ability to penetrate the phospholipid bilayer of the cell membrane. These modifications, known as prodrug strategies, involve derivatizing the drug substance by introducing substituents that reduce the hydrophilicity of the molecule. The present mini-review outlines the examples of Christopher McGuigan’s prodrug strategies used to obtain antiviral nucleosides with enhanced bioavailability and activity. These strategies primarily involve forming and optimizing the structure of esters and amino acid esters, phosphoramidates, octadecyl phosphates, and bis-pivaloxymethyl phosphates. The review discusses the optimization of the phosphoramidate prodrug moiety of the SARS-CoV-2 antiviral nucleoside remdesivir in detail. It presents the resulting improvement in bioavailability and antiviral activity. Moreover, it focuses on the modern prodrug strategy as one of the major recent advances in drug substance development. This strategy effectively optimized physicochemical properties and improved the functional activity of the existing drug substances and drug substance candidates for the first time.

Downloads

Download data is not yet available.

References

Tiz DB, Bagnoli L, Rosati O, Marini F, Santi C, Sancineto L. FDA-Approved Small Molecules in 2022: Clinical Uses and Their Synthesis. Pharmaceutics. 2022;14:2538. doi: org/10.3390/ pharmaceutics14112538. PMID: 36432728.

Wang K, Li Y, Chen B, Chen H, Smith DE, Sun D, Feng MR, Amidon GL. In Vitro Predictive Dissolution Test Should Be Developed and Recommended as a Bioequivalence Standard for the Immediate-Release Solid Oral Dosage Forms of the Highly Variable Mycophenolate Mofetil. Mol Pharm. 2022;19(7):2048-2060. doi: 10.1021/acs.molpharmaceut.1c00792. PMID: 35603895.

Markovic M, Ben-Shabat S, Dahan A. Prodrugs for Improved Drug Delivery: Lessons Learned from Recently Developed and Marketed Products. Pharmaceutics. 2020 Oct 29;12(11):1031. doi: 10.3390/pharmaceutics12111031. PMID: 33137942.

Zarzar J, Khan T, Bhagawati M, Weiche B, Sydow-Andersen J, Alavattam S. High-concentration formulation developability approaches and considerations. MAbs. 2023 Jan-Dec;15(1):2211185. doi: 10.1080/19420862.2023.2211185. PMID: 37191233.

Paul S, Gray D, Caswell J, Brooks J, Ye W, Moody TS, Radinov R, Nechev L. Convergent Biocatalytic Mediated Synthesis of siRNA. ACS Chem Biol. 2023 Apr 16. doi: 10.1021/acschembio.3c00071. PMID: 37061926.

Heidel KM, Dowd CS. Phosphonate prodrugs: an overview and recent advances. Future Med Chem. 2019 Jul;11(13):1625-1643. doi: 10.4155/fmc-2018-0591. PMID:

Bolla G, Sarma B, Nangia AK. Crystal Engineering of Pharmaceutical Cocrystals in the Discovery and Development of Improved Drugs. Chem Rev. 2022;122(13):11514-11603. doi: 10.1021/acs.chemrev.1c00987. PMID: 35642550.

Majumder J, Minko T. Recent Developments on Therapeutic and Diagnostic Approaches for COVID-19. AAPS J . 2021 Jan 5;23(1):14. doi: 10.1208/s12248-020-00532-2. PMID: 33400058.

Piscotta FJ, Hoffmann HH, Choi YJ, Small GI, Ashbrook AW, Koirala B, Campbell EA, Darst SA, Rice CM, Brady SF. Metabolites with SARS-CoV-2 Inhibitory Activity Identified from Human Microbiome Commensals. mSphere. 2021 Dec 22;6(6):e0071121. doi: 10.1128/mSphere.00711-21. PMID: 34851166.

Kleiner VA, O Fischmann T, Howe JA, Beshore DC, Eddins MJ, Hou Y, Mayhood T, Klein D, Nahas DD, Lucas BJ, Xi H, Murray E, Ma DY, Getty K, Fearns R. Conserved allosteric inhibitory site on the respiratory syncytial virus and human metapneumovirus RNA-dependent RNA polymerases. Commun Biol. 2023 Jun 19;6(1):649. doi: 10.1038/s42003-023-04990-0. PMID: 37337079.

Garcia G Jr, Irudayam JI, Jeyachandran AV, Dubey S, Chang C, Cario SC, Price N, Arumugam S, Marquez AL, Shah A, Fanaei A, Chakravarty N, Joshi S, Sinha S, French SW, Parcells M, Ramaiah A, Arumugaswami V. Broad-spectrum antiviral inhibitors targeting pandemic potential RNA viruses. bioRxiv . 2023 Jan 20. doi: 10.1101/2023.01.19.524824. Update in: Cell Rep Med. 2023 May 16;4(5):101024. PMID: 36711787.

Krečmerová M, Majer P, Rais R, Slusher BS. Phosphonates and Phosphonate Prodrugs in Medicinal Chemistry: Past Successes and Future Prospects. Front Chem. 2022 May 20;10:889737. doi: 10.3389/fchem.2022.889737. PMID: 35668826.

Shah VP, Amidon GL. G.L. Amidon. H. Lennernas, V.P. Shah, and J.R. Crison. A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of In Vitro Drug Product Dissolution and In Vivo Bioavailability, Pharm Res. 12, 413–420, 1995—Backstory of BCS. AAPS J. 2014 September 16 (5) (# 2014) doi: 10.1208/s12248-014-9620-9. PMID: 24961917.

Amidon GL, Lennernäs H, Shah V P, Crison J R. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995 Mar;12(3):413-20.

doi: 10.1023/a:1016212804288. PMID: 7617530.

Cahard D, McGuigan C, Balzarini J. Aryloxy phosphoramidate triesters as pro-tides. Mini Rev Med Chem. 2004 May;4(4):371-81. doi: 10.2174/1389557043403936. PMID: 15134540.

Kandil S, Balzarini J, Rat S, Brancale A, Westwell AD, McGuigan C. ProTides of BVdU as potential anticancer agents upon efficient intracellular delivery of their activated metabolites. Bioorg Med Chem Lett. 2016 Dec 1;26(23):5618-5623. doi: 10.1016/j.bmcl.2016.10.077. PMID: 27818111.

Roy B, Navarro V, Peyrottes S. Prodrugs of Nucleoside 5'-Monophosphate Analogues: Overview of the Recent Literature Concerning their Synthesis and Applications. Curr Med Chem. 2023;30(11):1256-1303. doi: 10.2174/0929867329666220909122820. PMID: 36093825.

Binderup A, Galli A, Fossat N, Fernandez-Antunez C, Mikkelsen LS, Rivera-Rangel LR, Scheel TKH, Fahnøe U, Bukh J, Ramirez S. Differential activity of nucleotide analogs against tick-borne encephalitis and yellow fever viruses in human cell lines. Virology. 2023 Jun 13;585:179-185. doi: 10.1016/j.virol.2023.06.002. PMID: 37356253.

Li L, Zhou J, Li Y, Wang F, Zhang D, Wang M, Tao Y, Chen E. Effectiveness and safety of tenofovir amibufenamide and its comparison with tenofovir alafenamide in patients with chronic hepatitis B: results from a retrospective real-world study. Front Pharmacol. 2023 Jun 1;14:1165990. doi: 10.3389/fphar.2023.1165990. PMID: 37324480.

Vargas DF, Larghi EL, Kaufman TS. Evolution of the Synthesis of Remdesivir. Classical Approaches and Most Recent Advances. ACS Omega. 2021 Jul 23;6(30):19356-19363. doi: 10.1021/acsomega.1c03082. PMID: 34368522.

Singh US, Konreddy AK, Kothapalli Y, Liu D, Lloyd MG, Annavarapu V, White CA, Bartlett MG, Moffat JF, Chu CK. Prodrug Strategies for the Development of β-l-5-((E)-2-Bromovinyl)-1-((2S,4S)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl))uracil (l-BHDU) against Varicella Zoster Virus (VZV). J Med Chem. 2023 May 25;66(10):7038-7053. doi: 10.1021/acs.jmedchem.3c00545. PMID: 37140467.

Hu H, Mady Traore MD, Li R, Yuan H, He M, Wen B, Gao W, Jonsson CB, Fitzpatrick EA, Sun D. Optimization of the Prodrug Moiety of Remdesivir to Improve Lung Exposure/Selectivity and Enhance Anti-SARS-CoV-2 Activity. J Med Chem. 2022 Sep 22;65(18):12044-12054. doi: 10.1021/acs.jmedchem.2c00758. PMID: 36070561.