172922-31-5Relevant articles and documents
Azole endothelin antagonists. 3. Using Δ log P as a tool to improve absorption
Von Geldern, Thomas W.,Hoffman, Daniel J.,Kester, Jeffrey A.,Nellans, Hugh N.,Dayton, Brian D.,Calzadilla, Samuel V.,Marsh, Kennan C.,Hernandez, Lisa,Chiou, William,Dixon, Douglas B.,Wu-Wong, Jinshyun R.,Opgenorth, Terry J.
, p. 982 - 991 (2007/10/03)
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 Δ log P. Comparison of urea 2 with a series of well-absorbed compounds using A 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 ET(A)-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 NS groups which simultaneously improve both potency and drug absorption. A combination of these optimized modifications produces carbamate 16h, a highly-selective ET(A) antagonist with a potency/bioavailability profile consistent with an oral route of administration.
