[(Aminomethyl)aryloxy]acetic acid esters. A new class of high-ceiling diuretics. 3. Variation in the bridge between the aromatic rings to complete mapping of the receptor

• Published in: Journal of medicinal chemistry Vol. 28; no. 1; pp. 79 - 93
• Main Authors: Plattner, Jacob J, Martin, Yvonne C, Smital, Jill R, Lee, Cheuk Man, Fung, Anthony K. L, Horrom, Bruce W, Crowley, Steven R, Pernet, Andre G, Bunnell, Paul R, Kim, Ki H
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.01.1985
• Subjects: Animals; Diuresis - drug effects; Diuretics - chemical synthesis; Glycolates - chemical synthesis; Glycolates - pharmacology; Mathematics; Methylamines - chemical synthesis; Methylamines - pharmacology; Models, Molecular; Optical Rotation; Rats; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00379a016

Continued structural evaluation of the [(aminomethyl)aryloxy]acetic ester diuretics has produced a series of compounds in which the functional group that bridges the two aromatic rings has been varied. Diuretic screening of these analogues in rats indicates that the keto group can be effectively replaced with an ether or thio ether function with a slight increase in potency, whereas the methylene and sulfoxide linking groups lead to diminished saluretic potency. Replacement with either -SO2-, -COCO-, -CH2O-, -CONH- or direct bond results in a loss of activity. Although the series was designed according to QSAR criteria, the traditional linear free-energy properties of these compounds do not correlate with diuretic potency. However, conformational analysis of the series by potential energy calculations indicates that all active compounds have an accessible conformation that matches the bridge atom-carboxylate distance of the very potent dihydrobenzofuran analogue 56. Conformational calculations of several compounds in which the aminomethyl group was varied suggests that the active conformation is probably a low-energy conformation. Consideration of rotation about the bridge could not distinguish between two possible orientations of the aminomethyl ring in the active conformation. However, there is a quantitative negative linear correlation between diuretic potency and the protrusion into space of the group that bridges the two aromatic rings.