A review is made of the literature describing the structural changes to glycyrrhetic, oleanolic and ursolic
acids and their influence on anti-
ulcer activity. For the
glycyrrhetic acid derivatives some analogues were prepared in which the ketonic group in position 11 was removed and the carboxylic function at position 30 was either intact, reduced to alcohol or transformed into
ketone. This first series of compounds suggests the possibility of obtaining compounds devoid of the conjugated ketonic group, maintaining anti-
ulcer activity but with reduced or lacking
mineralocorticoid activity. Based on these findings, a series of
carbenoxolone analogues in the
beta-amyrin series of glycyrrhetic and
oleanolic acid was prepared. In particular, the delta 9,11 unsaturated compounds 14b and 23b and the 11-methylene derivative 18 present advantages in terms of acute toxicity and
mineralocorticoid activity as compared to the reference compound. The derivative 14b in the volunteer showed an increase of gastric
PGE2 levels with minor pseudoaldosteronic effect. Among the
ursolic acid derivatives, the dihemisuccinate
sodium salt 35b demonstrated a good separation between anti-
ulcer and
mineralocorticoid activities. Nevertheless, kidney and liver toxicity was observed in the monkey thus jeopardizing its further development. Better results were obtained with the
uvaol dihemiphthalate
sodium salt and the diene analogue 39b. In particular, 38b and 39b showed a potent anti-
ulcer activity, 3- to 25-fold higher than
carbenoxolone. Furthermore, compound 38b does not show signs of liver toxicity in the monkey.