ArticleJournal of medicinal chemistry2010
Enhancing the intestinal absorption of molecules containing the polar guanidino functionality: a double-targeted prodrug approach.
Article in Journal of medicinal chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- Breast Cancer: Challenges in the Treatment and Prodrug Strategies.Mini reviews in medicinal chemistry · 2026Review
- A Novel Prodrug Strategy Based on Reversibly Degradable Guanidine Imides for High Oral Bioavailability and Prolonged Pharmacokinetics of Broad-Spectrum Anti-influenza Agents.ACS central science · 2024Article
- The landscape of small-molecule prodrugs.Nature reviews. Drug discovery · 2024Review
- Novel Psilocin Prodrugs with Altered Pharmacological Properties as Candidate Therapies for Treatment-Resistant Anxiety Disorders.Journal of medicinal chemistry · 2024Article
- Prodrug Therapies for Infectious and Neurodegenerative Diseases.Pharmaceutics · 2022Review
- Prodrugs for Improved Drug Delivery: Lessons Learned from Recently Developed and Marketed Products.Pharmaceutics · 2020Review
- Computational Simulations to Guide Enzyme-Mediated Prodrug Activation.International journal of molecular sciences · 2020Review
- A novel oral prodrug-targeting transporter MCT 1: 5-fluorouracil-dicarboxylate monoester conjugates.Asian journal of pharmaceutical sciences · 2019Article
- Computational modeling and in-vitro/in-silico correlation of phospholipid-based prodrugs for targeted drug delivery in inflammatory bowel disease.Journal of computer-aided molecular design · 2017Article
- Enzymatic activation of double-targeted 5'-O-L-valyl-decitabine prodrug by biphenyl hydrolase-like protein and its molecular design basis.Drug delivery and translational research · 2017Article
- Carrier-Mediated Prodrug Uptake to Improve the Oral Bioavailability of Polar Drugs: An Application to an Oseltamivir Analogue.Journal of pharmaceutical sciences · 2016Article
- Hydrotropic Solubilization of Lipophilic Drugs for Oral Delivery: The Effects of Urea and Nicotinamide on Carbamazepine Solubility-Permeability Interplay.Frontiers in pharmacology · 2016Article
- Modern prodrug design for targeted oral drug delivery.Molecules (Basel, Switzerland) · 2014Article
- Provisional in-silico biopharmaceutics classification (BCS) to guide oral drug product development.Drug design, development and therapy · 2014Article
- Significance of peptide transporter 1 in the intestinal permeability of valacyclovir in wild-type and PepT1 knockout mice.Drug metabolism and disposition: the biological fate of chemicals · 2013Article
- The rationality for using prodrug approach in drug discovery programs for new xenobiotics: opportunities and challenges.European journal of drug metabolism and pharmacokinetics · 2011Review
- Specificity of a prodrug-activating enzyme hVACVase: the leaving group effect.Molecular pharmaceutics · 2010Article
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3 authors.
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Abstract
A prodrug strategy was applied to guanidino-containing analogues to increase oral absorption via hPEPT1 and hVACVase. l-Valine, l-isoleucine, and l-phenylalanine esters of [3-(hydroxymethyl)phenyl]guanidine (3-HPG) were synthesized and evaluated for transport and activation. In HeLa/hPEPT1 cells, Val-3-HPG and Ile-3-HPG exhibited high affinity to hPEPT1 (IC(50): 0.65 and 0.63 mM, respectively), and all three l-amino acid esters showed higher uptake (2.6- to 9-fold) than the parent compound 3-HPG. Val-3-HPG and Ile-3-HPG demonstrated remarkable Caco-2 permeability enhancement, and Val-3-HPG exhibited comparable permeability to valacyclovir. In rat perfusion studies, Val-3-HPG and Ile-3-HPG permeabilities were significantly higher than 3-HPG and exceeded/matched the high-permeability standard metoprolol, respectively. All the l-amino acid 3-HPG esters were effectively activated in HeLa and Caco-2 cell homogenates and were found to be good substrates of hVACVase (k(cat)/K(m) in mM(-1) x s(-1): Val-3-HPG, 3370; Ile-3-HPG, 1580; Phe-3-HPG, 1660). In conclusion, a prodrug strategy is effective at increasing the intestinal permeability of polar guanidino analogues via targeting hPEPT1 for transport and hVACVase for activation.
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