ArticleBioconjugate chemistry2010
Structural requirements of the ASBT by 3D-QSAR analysis using aminopyridine conjugates of chenodeoxycholic acid.
Article in Bioconjugate chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 17 citations in OpenAlex.
- Transporter-Mediated Drug Delivery.Molecules (Basel, Switzerland) · 2023Review
- Bile acid transporter-mediated oral drug delivery.Journal of controlled release : official journal of the Controlled Release Society · 2020Review
- Intestinal Absorption of Bile Acids in Health and Disease.Comprehensive Physiology · 2019Review
- SLC Transporters: Structure, Function, and Drug Discovery.MedChemComm · 2016Article
- SLC transporters as therapeutic targets: emerging opportunities.Nature reviews. Drug discovery · 2015Review
- Mechanistic interpretation of conventional Michaelis-Menten parameters in a transporter system.European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences · 2014Article
- An updated review on drug-induced cholestasis: mechanisms and investigation of physicochemical properties and pharmacokinetic parameters.Journal of pharmaceutical sciences · 2013Review
- Structure-activity relationship for FDA approved drugs as inhibitors of the human sodium taurocholate cotransporting polypeptide (NTCP).Molecular pharmaceutics · 2013Article
- 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
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5 authors at 1 institution in 1 country.
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Abstract
The human apical sodium-dependent bile acid transporter (ASBT) is a validated drug target and can be employed to increase oral bioavailability of various drug conjugates. The aim of the present study was to investigate the chemical space around the 24-position of bile acids that influences both inhibition and uptake by the transporter. A series of 27 aminopyridine and aminophenol conjugates of glutamyl-chenodeoxycholate were synthesized and their ASBT inhibition and transport kinetics (parametrized as K(i), K(t), and J(max)) measured using stably transfected ASBT-MDCK cells. All conjugates were potent ASBT inhibitors. Monoanionic conjugates exhibited higher inhibition potency than neutral conjugates. However, neutral conjugates and chloro-substituted monoanionic conjugates were not substrates, or at least not apparent substrates. Kinetic analysis of substrates indicated that similar values for K(i) and K(t) implicate substrate binding to ASBT as the rate-limiting step. Using 3D-QSAR, four inhibition models and one transport efficiency model were developed. Steric fields dominated in CoMFA models, whereas hydrophobic fields dominated CoMSIA models. The inhibition models showed that a hydrophobic or bulky substitute on the 2 or 6 position of a 3-aminopyridine ring enhanced activity, while a hydrophobic group on the 5 position was detrimental. Overall, steric and hydrophobic features around the 24 position of the sterol nucleus strongly influenced bile acid conjugate interaction with ASBT. The relative location of the pyridine nitrogen and substituent groups also modulated binding.
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