Discovery of 4'-[(imidazol-1-yl)methyl]biphenyl-2-sulfonamides as dual endothelin/angiotensin II receptor antagonists.
A series of 4'-[(imidazol-1-yl)methyl]biphenylsulfonamides has potent antagonist activity against both angiotensin II AT(1) and endothelin ET(A) receptors. Such dual-acting antagonists could have utility in the treatment of hypertension, heart failure, and other cardiovascular diseases in a broad patient population. Certain compounds in the present series are orally active in a rat model of angiotensin II-mediated hypertension.
Tellew
John E
JE
Department of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-5400, USA. jtellew@neurocrine.com
Baska
Rose Ann F
RA
Beyer
Sophie M
SM
Carlson
Kenneth E
KE
Cornelius
Lyndon A
LA
Fadnis
Leena
L
Gu
Zhengxiang
Z
Kunst
Bridgette L
BL
Kowala
Mark C
MC
Monshizadegan
Hossain
H
Murugesan
Natesan
N
Ryan
Carol S
CS
Valentine
Maria T
MT
Yang
Yifan
Y
Macor
John E
JE
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D018938:Caco-2 Cells; D015195:Drug Design; D065128:Endothelin Receptor Antagonists; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D007202:Indicators and Reagents; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044022:Receptor, Endothelin A; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D065128:Endothelin Receptor Antagonists; D007093:Imidazoles; D007202:Indicators and Reagents; D044140:Receptor, Angiotensin, Type 1; D044022:Receptor, Endothelin A; D013449:Sulfonamides