1025962-46-2Relevant academic research and scientific papers
Azole endothelin antagonists. 2. Structure-activity studies
Von Geldern, Thomas W.,Kester, Jeffrey A.,Bal, Radhika,Wu-Wong, Jinshyun R.,Chiou, William,Dixon, Douglas B.,Opgenorth, Terry J.
, p. 968 - 981 (2007/10/03)
Structure-activity studies have been performed in an attempt to improve the potency of a novel series of azole-based endothelin-A (ET(A)) selective antagonists. Modifications of the hydrophobic group on the terminal urea produced substantial effects on receptor affinity; in particular, the choice of cyclohexyl- or arylureas led to substantial improvements in activity. Conformational restriction of these groups provides an additional benefit. N- Methylation of the indole moiety which is part of the heterocyclic dipeptide surrogate also improves potency. The effects of these two modifications appear to be synergistic, with the best of the resultant doubly modified analogs (e.g. 14q, 15y, and 15ff) exhibiting an 80-200-fold improvement over the original leads.
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.
