Quinoxaline N-oxide containing potent angiotensin II receptor antagonists: synthesis, biological properties, and structure-activity relationships.
A series of novel quinoxaline heterocycle containing angiotensin II receptor antagonist analogs were prepared. This heterocycle was coupled to the biphenyl moiety via an oxygen atom linker instead of a carbon atom. Many of these analogs exhibit very potent activity and long duration of effect. Interestingly, the N-oxide quinoxaline analog was more potent than the nonoxidized quinoxaline as in the comparison of compounds 5 vs 30. In order to improve oral activity, the carboxylic acid function of these compounds was converted to the double ester. This change did result in an improvement in oral activity as represented by compound 44.
Kim
K S
KS
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000.
Qian
L
L
Bird
J E
JE
Dickinson
K E
KE
Moreland
S
S
Schaeffer
T R
TR
Waldron
T L
TL
Delaney
C L
CL
Weller
H N
HN
Miller
A V
AV
D000284:Administration, Oral; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011810:Quinoxalines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D011810:Quinoxalines; D011945:Receptors, Angiotensin