Abstract:
:New analogs of cyclic amino acid-conjugated bile acids were synthesized, and their physicochemical and biological properties were compared with those of natural analogs. Ursodeoxycholic acid was amidated with D-proline, L-proline, 4-hydroxy-L-proline, and 4-methoxy-L-proline. Hyocholic and hyodeoxycholic acids were amidated with L-proline. The physicochemical properties were similar to those of the natural analogs. All of them were highly stable toward enzymatic C-24 amide bond hydrolysis and 7-dehydroxylation. Their transport, metabolism, and effect on biliary lipid secretion were evaluated in bile fistula rat after intravenous infusion. All the analogs were secreted in bile unmodified. The 4-methoxy-L-proline derivative produced the highest secretion rate, much higher than those of all the other natural and synthetic analogs. This was associated with a selective reduction of cholesterol secretion with normal phospholipid secretion and choleresis. When coinfused, all the analogs were able to prevent the hepatotoxicity induced by intravenous taurochenodeoxycholic acid, as revealed by normal choleresis, alkaline phosphatase, and lactate dehydrogenase values in bile. Considering the overall data, 4-methoxy-L-proline, 4-hydroxy-L-proline, and L-proline derivatives of ursodeoxycholic acid were more potent than the natural analogs.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Roda A,Cerrè C,Manetta AC,Cainelli G,Umani-Ronchi A,Panunzio Mdoi
10.1021/jm9508503subject
Has Abstractpub_date
1996-05-24 00:00:00pages
2270-6issue
11eissn
0022-2623issn
1520-4804pii
jm9508503journal_volume
39pub_type
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