The review provides an overview of the approaches, applications, and methods for ester prodrugs. Ester prodrugs are pharmacologically inactive compounds in their original form but become active drugs on biotransformation within the body, which offers advantages concerning the solubility, stability, and targeted delivery of the active drug. Several approaches of ester prodrugs have been reviewed in this review, including simple ester prodrugs, amino acid ester prodrugs, sugar ester prodrugs, lipid ester prodrugs, and polymeric ester prodrugs. This review incorporates in vitro and in vivo methods as well as the characterization of physical and chemical properties for ester prodrugs, cell culture systems, enzymatic assays, and animal models—all of these having a very important bearing on the evaluation of stability, bioavailability, and efficacy for ester prodrugs. While the benefits of using ester prodrugs are significant, there are also disadvantages like instability, poor or variable enzymatic hydrolysis, and toxicity from released promoieties or by-products. This review discusses solutions to the various limitations that include enhancing stability with ionizable promoieties and using physiologically-based pharmacokinetic modeling. The review also highlights the application of ester prodrugs in neurological disorders, such as Parkinson’s disease, and the ongoing efforts to address the critical limitations in treatment efficacy. Future prodrug strategies are poised to advance significantly by harnessing diverse transport mechanisms across the blood-brain barrier and integrating nanotechnology.
References
[1]
Choudhary, D., Goykar, H., Kalyane, D., Sreeharsha, N. and Tekade, R.K. (2020) Prodrug Design for Improving the Biopharmaceutical Properties of Therapeutic Drugs. In: Tekade, R.K., Ed., TheFutureofPharmaceuticalProductDevelopmentandResearch, Elsevier, 179-226. https://doi.org/10.1016/b978-0-12-814455-8.00006-2
[2]
Dubey, S. and Valecha, V. (2014) Prodrugs: A Review. World Journal of Pharmaceutical Research, 3, 277-297.
[3]
Rautio, J., Kumpulainen, H., Heimbach, T., Oliyai, R., Oh, D., Järvinen, T., et al. (2008) Prodrugs: Design and Clinical Applications. Nature Reviews Drug Discovery, 7, 255-270. https://doi.org/10.1038/nrd2468
[4]
Zawilska, J.B., Wojcieszak, J. and Olejniczak, A.B. (2013) Prodrugs: A Challenge for the Drug Development. Pharmacological Reports, 65, 1-14. https://doi.org/10.1016/s1734-1140(13)70959-9
[5]
Testa, B. (2004) Prodrug Research: Futile or Fertile? Biochemical Pharmacology, 68, 2097-2106. https://doi.org/10.1016/j.bcp.2004.07.005
[6]
Hajnal, K., Gabriel, H., Aura, R., Erzsébet, V. and Blanka, S.S. (2016) Prodrug Strategy in Drug Development. Acta Medica Marisiensis, 62, 356-362. https://doi.org/10.1515/amma-2016-0032
[7]
Perez, C., Daniel, K.B. and Cohen, S.M. (2013) Evaluating Prodrug Strategies for Esterase‐triggered Release of Alcohols. ChemMedChem, 8, 1662-1667. https://doi.org/10.1002/cmdc.201300255
[8]
Hamada, Y. (2017) Recent Progress in Prodrug Design Strategies Based on Generally Applicable Modifications. Bioorganic & Medicinal Chemistry Letters, 27, 1627-1632. https://doi.org/10.1016/j.bmcl.2017.02.075
[9]
Wang, Z., Cheng, L.P., Zhang, X.H., Pang, W., Li, L. and Zhao, J.L. (2017) Design, Synthesis and Biological Evaluation of Novel Oseltamivir Derivatives as Potent Neuraminidase Inhibitors. Bioorganic & Medicinal Chemistry Letters, 27, 5429-5435. https://doi.org/10.1016/j.bmcl.2017.11.003
[10]
Vig, B.S., Huttunen, K.M., Laine, K. and Rautio, J. (2013) Amino Acids as Promoieties in Prodrug Design and Development. Advanced Drug Delivery Reviews, 65, 1370-1385. https://doi.org/10.1016/j.addr.2012.10.001
[11]
Huttunen, K.M. (2024) Improving Drug Delivery to the Brain: The Prodrug Approach. Expert Opinion on Drug Delivery, 21, 683-693. https://doi.org/10.1080/17425247.2024.2355180
[12]
Huttunen, K.M. (2018) Identification of Human, Rat and Mouse Hydrolyzing Enzymes Bioconverting Amino Acid Ester Prodrug of Ketoprofen. Bioorganic Chemistry, 81, 494-503. https://doi.org/10.1016/j.bioorg.2018.09.018
[13]
Thompson, B.R., Shi, J., Zhu, H. and Smith, D.E. (2020) Pharmacokinetics of Gemcitabine and Its Amino Acid Ester Prodrug Following Intravenous and Oral Administrations in Mice. Biochemical Pharmacology, 180, Article ID: 114127. https://doi.org/10.1016/j.bcp.2020.114127
[14]
Haddad, F., Sawalha, M., Khawaja, Y., Najjar, A. and Karaman, R. (2017) Dopamine and Levodopa Prodrugs for the Treatment of Parkinson’s Disease. Molecules, 23, Article 40. https://doi.org/10.3390/molecules23010040
[15]
Shimoda, K., Hamada, H. and Hamada, H. (2008) Chemo-Enzymatic Synthesis of Ester-Linked Taxol-Oligosaccharide Conjugates as Potential Prodrugs. Tetrahedron Letters, 49, 601-604. https://doi.org/10.1016/j.tetlet.2007.11.156
[16]
Zheng, Y., Zheng, M., Ma, Z., Xin, B., Guo, R. and Xu, X. (2015) Sugar Fatty Acid Esters. In: Ahmad, M.U. and Xu, X.B., Eds., PolarLipids, Elsevier, 215-243. https://doi.org/10.1016/b978-1-63067-044-3.50012-1
[17]
Zaro, J.L. (2014) Lipid-Based Drug Carriers for Prodrugs to Enhance Drug Delivery. The AAPS Journal, 17, 83-92. https://doi.org/10.1208/s12248-014-9670-z
[18]
Mura, S., Bui, D.T., Couvreur, P. and Nicolas, J. (2015) Lipid Prodrug Nanocarriers in Cancer Therapy. Journal of Controlled Release, 208, 25-41. https://doi.org/10.1016/j.jconrel.2015.01.021
[19]
Khandare, J. and Minko, T. (2006) Polymer-Drug Conjugates: Progress in Polymeric Prodrugs. Progress in Polymer Science, 31, 359-397. https://doi.org/10.1016/j.progpolymsci.2005.09.004
[20]
Li, Y., Ye, C., Cai, C., Zhao, M., Han, N., Liu, Z., et al. (2020) Design and Synthesis of Polymer Prodrugs for Improving Water-Solubility, Pharmacokinetic Behavior and Antitumor Efficacy of Txa9. Pharmaceutical Research, 37, Article No. 66. https://doi.org/10.1007/s11095-020-02789-w
[21]
Rautio, J., Meanwell, N.A., Di, L. and Hageman, M.J. (2018) The Expanding Role of Prodrugs in Contemporary Drug Design and Development. Nature Reviews Drug Discovery, 17, 559-587. https://doi.org/10.1038/nrd.2018.46
[22]
Lesniewska-Kowiel, M.A. and Muszalska, I. (2017) Strategies in the Designing of Prodrugs, Taking into Account the Antiviral and Anticancer Compounds. European Journal of Medicinal Chemistry, 129, 53-71. https://doi.org/10.1016/j.ejmech.2017.02.011
[23]
Miao, H., Chen, X. and Luan, Y. (2020) Small Molecular Gemcitabine Prodrugs for Cancer Therapy. Current Medicinal Chemistry, 27, 5562-5582. https://doi.org/10.2174/0929867326666190816230650
[24]
Dong, H., Pang, L., Cong, H., Shen, Y. and Yu, B. (2019) Application and Design of Esterase-Responsive Nanoparticles for Cancer Therapy. Drug Delivery, 26, 416-432. https://doi.org/10.1080/10717544.2019.1588424
[25]
Chen, W., Zhong, Y., Feng, N., Guo, Z., Wang, S. and Xing, D. (2021) New Horizons in the Roles and Associations of COX-2 and Novel Natural Inhibitors in Cardiovascular Diseases. Molecular Medicine, 27, Article No. 123. https://doi.org/10.1186/s10020-021-00358-4
[26]
Polhemus, D.J., Li, Z., Pattillo, C.B., Gojon, G., Gojon, G., Giordano, T., et al. (2015) A Novel Hydrogen Sulfide Prodrug, sg1002, Promotes Hydrogen Sulfide and Nitric Oxide Bioavailability in Heart Failure Patients. Cardiovascular Therapeutics, 33, 216-226. https://doi.org/10.1111/1755-5922.12128
[27]
Xia, X., Zhou, Y. and Gao, H. (2021) Prodrug Strategy for Enhanced Therapy of Central Nervous System Disease. Chemical Communications, 57, 8842-8855. https://doi.org/10.1039/d1cc02940a
[28]
He, X., Sugawara, M., Takekuma, Y. and Miyazaki, K. (2004) Absorption of Ester Prodrugs in Caco-2 and Rat Intestine Models. Antimicrobial Agents and Chemotherapy, 48, 2604-2609. https://doi.org/10.1128/aac.48.7.2604-2609.2004
[29]
Hong, X., Cai, Z., Zhou, F., Jin, X., Wang, G., Ouyang, B., et al. (2022) Improved Pharmacokinetics of Tenofovir Ester Prodrugs Strengthened the Inhibition of HBV Replication and the Rebalance of Hepatocellular Metabolism in Preclinical Models. Frontiers in Pharmacology, 13, Article 9329374. https://doi.org/10.3389/fphar.2022.932934
[30]
Hosokawa, M. (2008) Structure and Catalytic Properties of Carboxylesterase Isozymes Involved in Metabolic Activation of Prodrugs. Molecules, 13, 412-431. https://doi.org/10.3390/molecules13020412
[31]
Sun, H. (2012) Capture Hydrolysis Signals in the Microsomal Stability Assay: Molecular Mechanisms of the Alkyl Ester Drug and Prodrug Metabolism. Bioorganic&MedicinalChemistryLetters, 22, 989-995. https://doi.org/10.1016/j.bmcl.2011.12.005
[32]
Ratnatilaka Na Bhuket, P., Jithavech, P., Ongpipattanakul, B. and Rojsitthisak, P. (2019) Interspecies Differences in Stability Kinetics and Plasma Esterases Involved in Hydrolytic Activation of Curcumin Diethyl Disuccinate, a Prodrug of Curcumin. RSCAdvances, 9, 4626-4634. https://doi.org/10.1039/c8ra08594c
[33]
Vandamme, T. (2014) Use of Rodents as Models of Human Diseases. JournalofPharmacyandBioalliedSciences, 6, 2-9. https://doi.org/10.4103/0975-7406.124301
[34]
Padilla, A.M., Wang, W., Akama, T., Carter, D.S., Easom, E., Freund, Y., et al. (2022) Discovery of an Orally Active Benzoxaborole Prodrug Effective in the Treatment of Chagas Disease in Non-Human Primates. NatureMicrobiology, 7, 1536-1546. https://doi.org/10.1038/s41564-022-01211-y
[35]
Chen, L., Zhou, L., Huang, J., Wang, Y., Yang, G., Tan, Z., et al. (2018) Single-and Multiple-Dose Trials to Determine the Pharmacokinetics, Safety, Tolerability, and Sex Effect of Oral Ginsenoside Compound K in Healthy Chinese Volunteers. FrontiersinPharmacology, 8, Article 965. https://doi.org/10.3389/fphar.2017.00965
[36]
Cavallaro, G., Licciardi, M., Caliceti, P., Salmaso, S. and Giammona, G. (2004) Synthesis, Physico-Chemical and Biological Characterization of a Paclitaxel Macromolecular Prodrug. EuropeanJournalofPharmaceuticsandBiopharmaceutics, 58, 151-159. https://doi.org/10.1016/j.ejpb.2004.02.012
