Synthesis and Enzyme Hydrolysis Study of Acyloxyalkyl Carbamates as New Prodrugs for Amines
DOI:
https://doi.org/10.32947/ajps.v25i4.1155Keywords:
acyloxy alkyl carbamates, prodrugs, drug delivery, pharmacological efficacy, enzymatic activation, drug permeabilityAbstract
In this review, we examined studies through 2023 with particular attention to the cases listed below. by investigate the potential of acyloxyalkyl carbamates for the amine-containing drug in order to overcome problems associated with medication transport and pharmacological activity of these drugs by improving drug delivery and penetration for amine drugs.
This review explores how the esterase enzymes can generate effective parent drugs to give pharmacological action.
The findings focus on two main concepts. The first is activating enzymes and targeting their effects. The second concept focuses on creating pro-moieties that can achieve the intended outcome efficiently and how selecting the appropriate pro-moieties is crucial for creating stable compounds that do not produce any toxic byproducts. The review highlights the importance of enhancing drug solubility and permeability, particularly for amino-group prodrugs.
References
1- Dahan A, Zimmermann EM, Ben-Shabat S. Modern prodrug design for targeted oral drug delivery. Molecules. 2014;19(10):16489-505.
2- Markovic M, Deodhar S, Machhi J, Yeapuri P, Saleh M, J. Edagwa B, et al. Prodrug therapies for infectious and neurodegenerative diseases. Pharmaceutics. 2022;14(3):518.
3- Jana S, Mandlekar S, Marathe P. Prodrug design to improve pharmacokinetic and drug delivery properties: challenges to the discovery scientists. Current medicinal chemistry. 2010;17(32):3874-908.
4- Stella VJ, Nti-Addae KW. Prodrug strategies to overcome poor water solubility. Advanced drug delivery reviews. 2007;59(7):677-94.
5- Testa B. Prodrug research: futile or fertile? Biochemical pharmacology. 2004;68(11):2097-106.
6- Mahdi MF, Dawood AH, Hussein AK. Design, Synthesis and Preliminary Pharmacological Evaluation of Mutual Prodrug of Non-Steroidal Anti-Inflammatory Drugs Coupling With Natural Anti-Oxidants Via Glycine. Al Mustansiriyah Journal of Pharmaceutical Sciences. 2013;13(1):155-69.
7- Huttunen KM, Raunio H, Rautio J. Prodrugs—from serendipity to rational design. Pharmacological reviews. 2011;63(3):750-71.
8- Han H-K, Amidon GL. Targeted prodrug design to optimize drug delivery. Aaps Pharmsci. 2000;2:48-58.
9- Hu L. Prodrugs: effective solutions for solubility, permeability and targeting challenges. IDrugs. 2004;7(8):736-42.
10- Liederer BM, Borchardt RT. Enzymes involved in the bioconversion of ester-based prodrugs. Journal of pharmaceutical sciences. 2006;95(6):1177-95.
11- Stella VJ, Charman W, Naringrekar VH. Prodrugs: Do they have advantages in clinical practice? Drugs. 1985;29:455-73.
12- Stella V, Borchardt R, Hageman M, Oliyai R, Maag H, Tilley J. Prodrugs: challenges and rewards: Springer Science & Business Media; 2007.
13- Müller CE. Prodrug approaches for enhancing the bioavailability of drugs with low solubility. Chemistry & Biodiversity. 2009;6(11):2071-83.
14- Khazaal N, Taha M, Basim M, Amer H. Quick Pharmaceutical steps for preliminary evaluation of a compund as a possible oral prodrug. Al Mustansiriyah Journal of Pharmaceutical Sciences. 2011;9(1):1-6.
15- Silverman RB, Holladay MW. The organic chemistry of drug design and drug action: Academic press; 2014.
16- Amidon G, Leesman G, Elliott R. Improving intestinal absorption of water‐insoluble compounds: A membrane metabolism strategy. Journal of pharmaceutical sciences. 1980;69(12):1363-8.
17- Stella VJ. Prodrugs: Some thoughts and current issues. J Pharm Sci 99: 4755–4765. Journal of Pharmaceutical Sciences. 2011;100(10):4560.
18- Ettmayer P, Amidon GL, Clement B, Testa B. Lessons learned from marketed and investigational prodrugs. Journal of medicinal chemistry. 2004;47(10):2393-404.
19- Rautio J, Kumpulainen H, Heimbach T, Oliyai R, Oh D, Järvinen T, et al. Prodrugs: design and clinical applications. Nature reviews Drug discovery. 2008;7(3):255-70.
20- Abet V, Filace F, Recio J, Alvarez-Builla J, Burgos C. Prodrug approach: An overview of recent cases. European journal of medicinal chemistry. 2017;127:810-27.
21- Testa B. Prodrugs: bridging pharmacodynamic/pharmacokinetic gaps. Current opinion in chemical biology. 2009;13(3):338-44.
22- Hu L. The prodrug approach to better targeting. Current drug discovery. 2004(AUG.):28-32.
23- Buckley ST, Fischer SM, Fricker G, Brandl M. In vitro models to evaluate the permeability of poorly soluble drug entities: challenges and perspectives. European journal of pharmaceutical sciences. 2012;45(3):235-50.
24- Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced drug delivery reviews. 1997;23(1-3):3-25.
25- Sætern AM, Flaten GE, Brandl M. A method to determine the incorporation capacity of camptothecin in liposomes. Aaps Pharmscitech. 2004;5:30-7.
26- Nielsen P, Müllertz A, Norling T, Kristensen H. The effect of α-tocopherol on the in vitro solubilisation of lipophilic drugs. International journal of pharmaceutics. 2001;222(2):217-24.
27- Markovic M, Ben‐Shabat S, Keinan S, Aponick A, Zimmermann EM, Dahan A. Lipidic prodrug approach for improved oral drug delivery and therapy. Medicinal research reviews. 2019;39(2):579-607.
28- Kalgutkar AS, Marnett AB, Crews BC, Remmel RP, Marnett LJ. Ester and amide derivatives of the nonsteroidal antiinflammatory drug, indomethacin, as selective cyclooxygenase-2 inhibitors. Journal of medicinal chemistry. 2000;43(15):2860-70.
29- Gogate U, Repta A, Alexander J. N-(Acyloxyalkoxycarbonyl) derivatives as potential prodrugs of amines. I. Kinetics and mechanism of degradation in aqueous solutions. International journal of pharmaceutics. 1987;40(3):235-48.
30- Gogate U, Repta A. N-(Acyloxyalkoxycarbonyl) derivatives as potential prodrugs of amines. II. esterase-catalysed release of parent amines from model prodrugs. International journal of pharmaceutics. 1987;40(3):249-55.
31- Li Z, Bitha P, Lang Jr SA, Lin Y-I. Synthesis of (alkoxycarbonyloxy) methyl,(acyloxy) methyl and (oxodioxolenyl) methyl carbamates as bioreversible prodrug moieties for amines. Bioorganic & Medicinal Chemistry Letters. 1997;7(22):2909-12.
32- Bodor N. Prodrugs versus soft drugs In “Design of Prodrugs” H. Bundgard (ed) Elsevier, Amsterdam. 1985.
33- Zheng T, Nolan EM. Evaluation of (acyloxy) alkyl ester linkers for antibiotic release from siderophore–antibiotic conjugates. Bioorganic & Medicinal Chemistry Letters. 2015;25(21):4987-91.
34- Ghosh AK, Brindisi M. Organic carbamates in drug design and medicinal chemistry. Journal of medicinal chemistry. 2015;58(7):2895-940.
35- Matošević A, Bosak A. Carbamate group as structural motif in drugs: A review of carbamate derivatives used as therapeutic agents. Archives of Industrial Hygiene and Toxicology. 2020;71(4):285-99.
36- Alexander J, Fromtling RA, Bland JA, Pelak BA, Gilfillan EC. (Acyloxy) alkyl carbamate prodrugs of norfloxacin. Journal of medicinal chemistry. 1991;34(1):78-81.
37- Mulvihill MJ, Shaber SH, MacDougall BS, Ajello C, Martinez-Teipel B, Joseph R, et al. Synthesis of insecticidally active halofenozide-[(acyloxy) alkoxy] carbonyl and (acyloxy) alkyl derivatives. Synthesis. 2002;2002(01):0053-8.
38- Cundy KC, Branch R, Chernov-Rogan T, Dias T, Estrada T, Hold K, et al. XP13512 [(±)-1-([(α-Isobutanoyloxyethoxy) carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: I. Design, synthesis, enzymatic conversion to gabapentin, and transport by intestinal solute transporters. Journal of Pharmacology and experimental therapeutics. 2004;311(1):315-23.
Downloads
Published
Issue
Section
License
Copyright (c) 2025 Israa Abad Alrasol Mohamed Sadeq, Ali Rasool Mahmood Albakaa, Mohammed Al-Ameedee, Enageh A. A. Abdalgader
This work is licensed under a Creative Commons Attribution 4.0 International License.
How to Cite
