AZOLE ENDOTHELIN ANTAGONISTS .3. USING DELTA-LOG-P AS A TOOL TO IMPROVE ABSORPTION

The oral absorption profile of a family of azole-based ET(A)-selective antagonists has been improved through a rational series of structural modifications which were suggested by analysis of the physicochemical parameter Delta log P. Comparison of urea 2 with a series of well-abs orbed compounds using Delta log P analysis suggested that 2 has an exc ess capacity for forming hydrogen bonds with solvent. A series of urea modifications were explored as a means of reducing H-bonding capacity while maintaining affinity for the ET(A)-receptor. The correlation be tween Delta log P values and absorption in an intraduodenal (id) bioav ailability model was good; this strategy uncovered replacements for ea ch of the urea NH groups which simultaneously improve both potency and drug absorption. A combination of these optimized modifications produ ces carbamate 16h, a highly-selective ET(A) antagonist with a potency/ bioavailability profile consistent with an oral route of administratio n.