Liver-specific drug targeting by coupling to bile acids.

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.

Section: Interaction Of Bile Acids With the 3d Qsar Hypothesismentioning

confidence: 93%

Section: Interaction Of Bile Acids With the 3d Qsar Hypothesismentioning

confidence: 97%

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

“…After an initial bile collection period of 30 min, 500 l of a solution of the respective compounds (concentration usually 50 m) dissolved in 10 mm of Tris/HEPES buffer (pH 7.4) 300 mm mannitol, ethanol content Ͻ5% was injected as bolus into a peripheral mesenteric vein and bile was collected after 2, 4, 6, 8, 10, 15, 20 min and subsequently in 10-min steps until 120 min after the initial injection. In situ ileal perfusion with radiolabeled bile acid analogues was performed as described elsewhere (23,27,42).…”

Section: Liver Perfusion Experiments and In Situ Ileal Perfusionmentioning

confidence: 99%

“…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).…”

mentioning

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

101

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.

“…tion of lipids during food ingestion and their transport to the liver, recent studies suggest that they may be used to transport and target drugs to the liver (10,11). We report the synthesis, biliary secretion, and intestinal metabolism of the conjugate of ursodeoxycholic acid (UDCA) with 5-ASA (UDCA-5-ASA; Fig.…”

mentioning

confidence: 99%

Synthesis and intestinal metabolism of ursodeoxycholic acid conjugate with an antiinflammatory agent, 5-aminosalicylic acid

Batta

Tint

et al. 1998

5-Aminosalicylic acid conjugate of ursodeoxycholic acid was synthesized in above 90% yield by adding a basic solution of 5-aminosalicylic acid into the mixed anhydride formed with ursodeoxycholic acid and ethyl chloroformate. The 5-aminosalicylic acid conjugate of ursodeoxycholic acid was poorly secreted into the bile and was deconjugated with cholylglycine hydrolase and Clostridium perfringens, that deconjugate naturally occurring glycine and taurine conjugates of bile acids. However, ursodeoxycholic acid 5-aminosalicylic acid conjugate was not absorbed from the duodenum but was concentrated in the colon wher e it was partially hydrolyzed by the intestinal bacteria to ursodeoxycholic acid and 5-aminosalicylic acid. We believe that this unique conjugation of ursodeoxycholic acid with 5-aminosalicylic acid may facilitate the transpor t of both 5aminosalicylic acid and ursodeoxycholic acid to the colon and may be useful for the treatment of colonic inflammatory bowel diseases, ulcerative colitis and Crohn's disease.-Batta, A. K., G. S. Tint, G. Xu, S. Shefer, and G. Salen. Synthesis and intestinal metabolism of ursodeoxycholic acid conjugate with an antiinflammatory agent, 5-aminosalicylic acid.