Studies on Uricosuric Diuretics. 4. Three-Dimensional Structure-Activity Relationships and Receptor Mapping of (Aryloxy)acetic Acid Diuretics

Attempts to develop new (aryloxy)acetic acids with a better profile of diuretic and uricosuric activities as well as with fewer side effects have produced a series of compounds in which the ring system has been varied. Diuretic screening of these analogues in rats indicated that the great difference in the activity between these compounds might be ascribed to a difference in the ring system rather than that in the substituent effect and that the annulation hypothesis described before is not necessarily applicable to all of these compounds. This prompted us to study the relationship between the structure and the diuretic activity of the (aryloxy)acetic acids. An active model (receptor model) was created with the indanone moiety of R-(-)-3 and the dihydrobenzofuran-2-carboxylic acid moiety of S-(+)-4. The three-dimensional structure-activity study of known compounds 2-4, and 5a using the active model showed that the degree of fitting to the model is related to the diuretic activity of these compounds. This was also confirmed for compounds 6a, 6b, 9a, 10a, 11a, 12a, 13a, 14a, 15a, and 16a, and the relation between the structure and the diuretic activity was rationalized qualitatively. With these insights in mind, a modified receptor model was constructed. We believe that this model is useful for a prediction of the activity of compounds not yet synthesized as well as for designing new (aryloxy)acetic acid diuretics.