ArticlePharmaceutical research2009
Inhibition requirements of the human apical sodium-dependent bile acid transporter (hASBT) using aminopiperidine conjugates of glutamyl-bile acids.
Article in Pharmaceutical research, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 23 citations in OpenAlex.
- Advances in Pharmacological Activities, Biosynthesis, and Structural Modification of Ursodeoxycholic Acid (UDCA): A Review.Drug design, development and therapy · 2025Review
- Discovery of Novel Glucagon Receptor Antagonists Using Combined Pharmacophore Modeling and Docking.Iranian journal of pharmaceutical research : IJPR · 2018Article
- Synthesis and biological activity of some bile acid-based camptothecin analogues.Molecules (Basel, Switzerland) · 2014Article
- An updated review on drug-induced cholestasis: mechanisms and investigation of physicochemical properties and pharmacokinetic parameters.Journal of pharmaceutical sciences · 2013Review
- Structural requirements of bile acid transporters: C-3 and C-7 modifications of steroidal hydroxyl groups.European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences · 2012Article
- Consensus 3D model of μ-opioid receptor ligand efficacy based on a quantitative Conformationally Sampled Pharmacophore.The journal of physical chemistry. B · 2011Article
- Computational ligand-based rational design: Role of conformational sampling and force fields in model development.MedChemComm · 2011Article
- Recent advances in ligand-based drug design: relevance and utility of the conformationally sampled pharmacophore approach.Current computer-aided drug design · 2011Review
- Role of the intestinal bile acid transporters in bile acid and drug disposition.Handbook of experimental pharmacology · 2011Review
- Structural determinants for transport across the intestinal bile acid transporter using C-24 bile acid conjugates.Molecular pharmaceutics · 2010Article
- Structural requirements of the ASBT by 3D-QSAR analysis using aminopyridine conjugates of chenodeoxycholic acid.Bioconjugate chemistry · 2010Article
- Reliability of inhibition models to correctly identify type of inhibition.Pharmaceutical research · 2010Article
- Molecular switch controlling the binding of anionic bile acid conjugates to human apical sodium-dependent bile acid transporter.Journal of medicinal chemistry · 2010Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
purposeSynthesize aminopiperidine conjugates of glutamyl-bile acids (glu-BAs) and develop a hASBT inhibition model using the conformationally sampled pharmacophore (CSP) approach.
methodsglu-BAs aminopiperidine conjugates were synthesized. hASBT inhibition was measured as K(i). A CSP-SAR model was built using structural and physico-chemical descriptors and evaluated via cross-validation.
resultsTwenty-nine aminopiperidine conjugates were synthesized. All inhibited hASBT, with K(i) ranging from 0.95 to 31.8 muM. Amidation of the piperidine nitrogen slightly decreased activity, while replacement by a carbon increased potency. Esterification of the glutamic acid linker had a minor impact, suggesting that a negative charge around C-24 is not required for binding. Three quantitative CSP-SAR models were developed. The best model (r (2) = 0.813, Q (2) = 0.726) included two descriptors: angle between 7-OH, alpha-substituent and centroid of rings B and C, and electrostatic contribution to the solvation free-energy. The model successfully distinguished between compounds with K(i) < 16muM and K(i) > 16muM. Models indicated that hydrophobicity, alpha substituent orientation, and partially compacted side chain conformation promote inhibitory potency. Qualitative CSP-SAR analysis indicated that the presence of an internal salt bridge, resulting in a locked conformation of the side chain, yielded weaker inhibitors.
conclusionsAminopiperidine conjugates of glu-BAs were potent hASBT inhibitors. A predictive and robust CSP-SAR model was developed.
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