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-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.
von Geldern
T W
TW
Aging and Degenerative Diseases Research, Pharmaceutical Products Research Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
Hoffman
D J
DJ
Kester
J A
JA
Nellans
H N
HN
Dayton
B D
BD
Calzadilla
S V
SV
Marsh
K C
KC
Hernandez
L
L
Chiou
W
W
Dixon
D B
DB
Wu-Wong
J R
JR
Opgenorth
T J
TJ
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
D001381:Azepines; D001393:Azoles; D065128:Endothelin Receptor Antagonists; D007202:Indicators and Reagents; D007211:Indoles; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; C079574:FR 139317