Inhibition of ileal sodium-dependent bile acid transport by 2164U90.

Root, Carolyn; Smith, Clive A.; Winegar, Deborah A.; Brieaddy, Lawrence E.; Lewis, Michael C.

doi:10.1016/s0022-2275(20)39869-2

Cited by 38 publications

(15 citation statements)

References 27 publications

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“…As mentioned above, the training set of compounds used to generate a pharmacophore should exhibit chemical diversity. We therefore selected a training set of 17 structurally diverse bile acid reabsorption inhibitors which were either identified by screening of chemical libraries or by rational design (the dimeric bile acid analogues S 0960, PB-3 and S 1690 ( 17)) as well as published bile acid reabsorption inhibitors, the benzothiazepines S 0382 and S 0381 (11,18). The structures of the training set are shown in Fig.…”

Section: Compounds Of the "Training Set"mentioning

confidence: 99%

Substrate specificity of the ileal and the hepatic Na+/bile acid cotransporters of the rabbit. II. A reliable 3D QSAR pharmacophore model for the ileal Na+/bile acid cotransporter

Baringhaus¹,

Matter²,

Stengelin³

et al. 1999

Journal of Lipid Research

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To design a reliable 3D QSAR model of the intestinal Na ؉ /bile acid cotransporter, we have used a training set of 17 inhibitors of the rabbit ileal Na ؉ /bile acid cotransporter. The IC 50 values of the training set of compounds covered a range of four orders of magnitude for inhibition of [ 3 H]cholyltaurine uptake by CHO cells expressing the rabbit ileal Na ؉ /bile acid cotransporter allowing the generation of a pharmacophore using the CATALYST algorithm. After thorough conformational analysis of each molecule, CATALYST generated a pharmacophore model characterized by five chemical features: one hydrogen bond donor, one hydrogen bond acceptor, and three hydrophobic features. The 3D pharmacophore was enantiospecific and correctly estimated the activities of the members of the training set. The predicted interactions of natural bile acids with the pharmacophore model of the ileal Na ؉ /bile acid cotransporter explain exactly the experimentally found structureactivity relationships for the interaction of bile acids with the ileal Na ؉ /bile acid cotransporter ( Kramer et al. 1999. J. Lipid. Res. 40: 1604-1617). The natural bile acid analogues cholyltaurine, chenodeoxycholyltaurine, or deoxycholyltaurine were able to map four of the five features of the pharmacophore model: a ) the five-membered ring D and the methyl group at position 18 map one hydrophobic site and the 21-methyl group of the side chain maps a second hydrophobic site; b ) one of the ␣ -oriented hydroxyl groups at position 7 or 12 fits the hydrogen bond donor feature; c ) the negatively charged side chain acts as hydrogen bond acceptor; and d ) the hydroxy group at position 3 does not specifically map any of the five binding features of the pharmacophore model. The 3-hydroxy group of natural bile acids is not essential for interactions with ileal or hepatic Na ؉ / bile acid cotransporters. A modification of the 3-position of a natural bile acid molecule is therefore the preferred position for drug targeting strategies using bile acid transport pathways. -Baringhaus, K-H., H. Matter, S. Stengelin, and W. Kramer. Substrate specificity of the ileal and the hepatic Na ؉ /bile acid cotransporters of the rabbit. II. A reliable 3D QSAR pharmacophore model for the ileal Na ؉ /bile acid cotransporter.

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Section: Compounds Of the "Training Set"mentioning

confidence: 99%

Substrate specificity of the ileal and the hepatic Na+/bile acid cotransporters of the rabbit. II. A reliable 3D QSAR pharmacophore model for the ileal Na+/bile acid cotransporter

Baringhaus¹,

Matter²,

Stengelin³

et al. 1999

Journal of Lipid Research

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confidence: 99%

“…Several types of bile acid reabsorption inhibitors have been described ( − ). A benzothiazepine compound, 2164U90 (Figure ), has been shown to efficiently block bile acid uptake via the ileal transporter in both in vitro and in vivo models ( , ). This compound and analogous structures are competitive inhibitors of the ileal sodium/bile acid cotransporter, but no information on the site of interaction between transporter and drug has been presented.…”

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Identification of a Region of the Ileal-Type Sodium/Bile Acid Cotransporter Interacting with a Competitive Bile Acid Transport Inhibitor

et al. 2002

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Drug intervention that prevents reabsorption of circulating bile acids by the apical (ileal) sodium/bile acid cotransporter (ASBT) may be a promising new therapy for lowering of plasma cholesterol. 2164U90 is a benzothiazepine-based competitive inhibitor of bile acid transport with K(i) values of approximately 10 and 0.068 microM for the homologous human and mouse apical transporters, respectively. Hybrid human-mouse and mouse-human transporters were engineered to identify regions involved in this 150-fold difference in the inhibition constant for 2164U90. A mouse-human chimera with only the most C-terminal hydrophobic domain and the C-terminus of the transporter originating from the human variant was found to have a sensitivity to 2164U90 inhibition similar to that of the human transporter. Conversely, a human-mouse hybrid transporter encompassing the same C-terminal region from the mouse sequence but now inserted into the human sequence demonstrated the greater inhibition seen with the mouse wild type ASBT. Amino acid substitutions, individually or in combinations, of six candidate nonconserved residues between mouse and human transporters in this C-terminal domain showed replacements of Thr294 by Ser and Val295 by Ile to be responsible for the difference in the sensitivity toward 2164U90 seen between the species. The hamster apical SBAT encompassing Ser/Ile in these positions shared the lower sensitivity to 2164U90, as seen with the human ASBT, even though it is identical to the mouse SBAT in the remaining four positions of this region. In addition, the rat ASBT which is identical to the mouse ASBT in this domain also had the high sensitivity to 2164U90 inhibition found for the mouse ASBT. Methanethiosulfonates (MTS) are known to inactivate the sodium/bile acid transporters through alkylation of a cysteine in the most C-terminal hydrophobic domain (1). Inactivation of the human ASBT due to MTS modification of cysteine 270 was shown to be largely abolished when the transporter was preincubated with 2164U90, suggesting that the binding of this benzothiazepine is in the vicinity of position 270. Thus, the domain containing the two most C-terminal putative transmembrane regions of the SBATs, H8-H9, previously shown to constitute part of the binding pocket for bile acids, interacts also with the bile acid transport competitive inhibitor, 2164U90.

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“…None of these cholephilic substrates showed a significant interaction with the ileal Na ϩ /bile acid cotransport system in brush border membrane vesicles (BBMV) (21,22). Only bile acid derivatives were known to interfere with ileal bile acid transport (21)(22)(23)(24) and just recently non-bile acid-derived inhibitors of the ileal bile acid transporter have been reported (25).…”

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confidence: 99%

Substrate specificity of the ileal and the hepatic Na+/bile acid cotransporters of the rabbit. I. Transport studies with membrane vesicles and cell lines expressing the cloned transporters

Kramer¹,

Stengelin²,

Baringhaus³

et al. 1999

Journal of Lipid Research

102

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The substrate specificity of the ileal and the hepatic Na ؉ /bile acid cotransporters was determined using brush border membrane vesicles and CHO cell lines permanently expressing the Na ؉ /bile acid cotransporters from rabbit ileum or rabbit liver. The hepatic transporter showed a remarkably broad specificity for interaction with cholephilic compounds in contrast to the ileal system. The anion transport inhibitor diisothiocyanostilbene disulfonate (DIDS) is a strong inhibitor of the hepatic Na ؉ /bile acid cotransporter, but does not show any affinity to its ileal counterpart. Inhibition studies and uptake measurements with about 40 different bile acid analogues differing in the number, position, and stereochemistry of the hydroxyl groups at the steroid nucleus resulted in clear structure-activity relationships for the ileal and hepatic bile acid transporters. The affinity to the ileal and hepatic Na ؉ /bile acid cotransport systems and the uptake rates by cell lines expressing those transporters as well as rabbit ileal brush border membrane vesicles is primarily determined by the substituents on the steroid nucleus. Two hydroxy groups at position 3, 7, or 12 are optimal whereas the presence of three hydroxy groups decreased affinity. Vicinal hydroxy groups at positions 6 and 7 or a shift of the 7-hydroxy group to the 6-position significantly decreased the affinity to the ileal transporter in contrast to the hepatic system. 6-Hydroxylated bile acid derivatives are preferred substrates of the hepatic Na ؉ /bile acid cotransporter. Surprisingly, the 3 ␣ -hydroxy group being present in all natural bile acids is not essential for high affinity interaction with the ileal and the hepatic bile acid transporter. The 3 ␣ -hydroxy group seems to be necessary for optimal transport of a bile acid across the hepatocyte canalicular membrane. A modification of bile acids at the 3-position therefore conserves the bile acid character thus determining the 3-position of bile acids as the ideal position for drug targeting strategies using bile acid transport pathways.

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Inhibition of ileal sodium-dependent bile acid transport by 2164U90.

Cited by 38 publications

References 27 publications

Substrate specificity of the ileal and the hepatic Na+/bile acid cotransporters of the rabbit. II. A reliable 3D QSAR pharmacophore model for the ileal Na+/bile acid cotransporter

Substrate specificity of the ileal and the hepatic Na+/bile acid cotransporters of the rabbit. II. A reliable 3D QSAR pharmacophore model for the ileal Na+/bile acid cotransporter

Identification of a Region of the Ileal-Type Sodium/Bile Acid Cotransporter Interacting with a Competitive Bile Acid Transport Inhibitor

Substrate specificity of the ileal and the hepatic Na+/bile acid cotransporters of the rabbit. I. Transport studies with membrane vesicles and cell lines expressing the cloned transporters

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