title: Azole endothelin antagonists. 3. Using delta log P as a tool to improve absorption.
abstract: 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-absorbed compounds using delta 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 delta 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 ET(A) antagonist with a potency/bioavailability profile consistent with an oral route of administration.
authors.affiliation: Aging and Degenerative Diseases Research, Pharmaceutical Products Research Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
authors.forename: T W
authors.initials: TW
authors.lastname: von Geldern
authors.forename: D J
authors.initials: DJ
authors.lastname: Hoffman
authors.forename: J A
authors.initials: JA
authors.lastname: Kester
authors.forename: H N
authors.initials: HN
authors.lastname: Nellans
authors.forename: B D
authors.initials: BD
authors.lastname: Dayton
authors.forename: S V
authors.initials: SV
authors.lastname: Calzadilla
authors.forename: K C
authors.initials: KC
authors.lastname: Marsh
authors.forename: L
authors.initials: L
authors.lastname: Hernandez
authors.forename: W
authors.initials: W
authors.lastname: Chiou
authors.forename: D B
authors.initials: DB
authors.lastname: Dixon
authors.forename: J R
authors.initials: JR
authors.lastname: Wu-Wong
authors.forename: T J
authors.initials: TJ
authors.lastname: Opgenorth
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001381:Azepines / Q000493:pharmacokinetics; D001393:Azoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D015195:Drug Design; D065128:Endothelin Receptor Antagonists; D006860:Hydrogen Bonding; D007202:Indicators and Reagents; D007211:Indoles / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D007700:Kinetics; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001381:Azepines; D001393:Azoles; D065128:Endothelin Receptor Antagonists; D007202:Indicators and Reagents; D007211:Indoles; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; C079574:FR 139317