SYNTHESIS AND PHYSICOCHEMICAL, BIOLOGICAL, AND PHARMACOLOGICAL PROPERTIES OF NEW BILE-ACIDS AMIDATED WITH CYCLIC AMINO-ACIDS

New analogs of cyclic amino acid-conjugated bile acids were synthesize d, and their physicochemical and biological properties were compared w ith those of natural analogs. Ursodeoxycholic acid was amidated with D -proline, L-proline, 4-hydroxy-L-proline, and 4-methoxy-L-proline. Hyo cholic and hyodeoxycholic acids were amidated with L-proline. The phys icochemical properties were similar to those of the natural analogs. A ll of them were highly stable toward enzymatic C-24 amide bond hydroly sis and 7-dehydroxylation. Their transport, metabolism, and effect on biliary lipid secretion were evaluated in bile fistula rat after intra venous infusion. All the analogs were secreted in bile unmodified. The 4-methoxy-L-proline derivative produced the highest secretion rate, m uch higher than those of all the other natural and synthetic analogs. This was associated with a selective reduction of cholesterol secretio n with normal phospholipid secretion and choleresis. When coinfused, a ll the analogs were able to prevent the hepatotoxicity induced by intr avenous taurochenodeoxycholic acid, as revealed by normal choleresis, alkaline phosphatase, and lactate dehydrogenase values in bile. Consid ering the overall data, 4-methoxy-L-proline, 4-hydroxy-L-proline, and L-proline derivatives of ursodeoxycholic acid were more potent than th e natural analogs.