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Kågedahl, Matts; Swaan, Peter W.; Redemann, Carl T.; Tang, Mary Y.; Craik, Charles S.; Szoka, Francis C.; Oie, Shigeharu

doi:10.1023/a:1012044526054

Cited by 38 publications

(15 citation statements)

References 10 publications

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“…C-24 bile acid conjugates have previously been shown to be ASBT substrates (7,29–31). One of these studies was a SAR study involving a series of C-24 cholic acid conjugates and found that the C-24 side chain can be 14 Å in length or longer for translocation, and that large hydrophobic moieties increase binding to ASBT (29).…”

Section: Resultsmentioning

confidence: 99%

Structural Requirements of the ASBT by 3D-QSAR Analysis Using Aminopyridine Conjugates of Chenodeoxycholic Acid

et al. 2010

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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 (parameterized as Ki, Kt, and Jmax) 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 Ki and Kt 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 2 or 6 position of a 3-aminopyridine ring enhanced activity, while a hydrophobic group on 5 position was detrimental. Overall, steric and hydrophobic features around the 24 position of the sterol nucleus strongly influenced bile acid conjugates’ interaction with ASBT. The relative location of the pyridine nitrogen and substituent groups also modulated binding.

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Section: Resultsmentioning

confidence: 99%

Structural Requirements of the ASBT by 3D-QSAR Analysis Using Aminopyridine Conjugates of Chenodeoxycholic Acid

et al. 2010

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“…The splitting of proton resonances in the 1 H NMR spectra are defined as s = singlet, d = doublet, and m = multiplet. 13 C NMR spectra were recorded on a Varian 400 NMR spectrometer ( 13 C at 100.57). Peak positions shown are relative to tetramethylsilane.…”

Section: Generalmentioning

confidence: 99%

“…Bile acids comprise a large group of natural or semi-synthetic molecules that are readily available at low cost; they have been used for pharmaceutical purposes for a long time, because of their known value as drug carriers [13]. Bile acid transport in the gastrointestinal tract is recognized as being an efficient high capacity system because of its involvement in reabsorption of bile salts following fat digestion.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, characterization of strontium-bile acid salts and their bioactivity vs. the anti-osteoporosis drug strontium ranelate

Bergamini

Marchesi

Pagnoni

et al. 2009

Journal of Inorganic Biochemistry

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“…To investigate the ability of the human intestinal bile acid transporter to transport cholic acid conjugates with potential HIV-1 protease inhibitory activity, cholic acid was conjugated at the 24 position of the sterol nucleus with various amino acids and amino acid analogues such as 53 ( Fig. 12) [79]. In this study, one amino acid analog-cholic acid conjugate showed HIV-1 protease inhibitory activity.…”

Section: Steroid-amino Acid Conjugatesmentioning

confidence: 99%

Steroidal Conjugates and Their Pharmacological Applications

Salunke

Hazra²,

Pore³

2006

CMC

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Nature continues to be the main source of inspiration for synthetic chemists in their quest to make novel conjugates, which can have different physical, biological and medicinal properties. Nature makes these conjugates from mixed biosynthesis and some of these chimeras are found to exhibit unusual biological properties. During the past two decades design of such entities has been receiving increasing attention. Among the hybrid natural products, hybrids of steroid frameworks have attracted great attention due to the significant biological properties and numerous therapeutic effects of steroids. The developments made over the past few years in the isolation, design and synthesis of steroidal conjugates and their pharmacological applications are discussed in this review.

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Cited by 38 publications

References 10 publications

Structural Requirements of the ASBT by 3D-QSAR Analysis Using Aminopyridine Conjugates of Chenodeoxycholic Acid

Structural Requirements of the ASBT by 3D-QSAR Analysis Using Aminopyridine Conjugates of Chenodeoxycholic Acid

Synthesis, characterization of strontium-bile acid salts and their bioactivity vs. the anti-osteoporosis drug strontium ranelate

Steroidal Conjugates and Their Pharmacological Applications

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