Azole Endothelin Antagonists. 3. Using Δ log P as a Tool To Improve Absorption

The oral absorption profile of a family of azole-based ETA-selective antagonists has been improved through a rational series of structural modifications which were suggested by analysis of the physicochemical parameter Δ log P. Comparison of urea 2 with a series of well-absorbed compounds using Δ log P analysis suggested that 2 has an excess 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 ETA-receptor. The correlation between Δ log P values and absorption in an intraduodenal (id) bioavailability model was good; this strategy uncovered replacements for each of the urea NH groups which simultaneously improve both potency and drug absorption. A combination of these optimized modifications produces carbamate 16h, a highly-selective ETA antagonist with a potency/bioavailability profile consistent with an oral route of administration.