Balanced AT1/AT2 receptor antagonists. 4. XR510 and related 5-(3-amidopropanoyl)imidazoles possessing equal affinity for the AT1 and AT2 receptors.
The identification of the AT1 and AT2 receptor subtypes has stimulated interest in developing balanced angiotensin II receptor antagonists. A series of 5-(3-amidopropanoyl)imidazoles has been prepared which possess balanced affinity for the AT1 and AT2 receptors. XR510 (1), 1-[[2'-[[(isopentoxycarbonyl)amino]sulfonyl]-3- fluoro(1,1'-biphenyl)-4-yl]methyl]-5-[3-(N-pyridin-3- ylbutanamido)propanoyl]-4-ethyl-2-propyl-1H-imidazole, potassium salt, exhibits subnanomolar affinity for both receptor sites. XR510 is very active in lowering blood pressure in renal hypertensive rats and furosemide-treated dogs following oral administration.
Quan
M L
ML
DuPont Merck Pharmaceutical Company, Experimental Station, Wilmington, Delaware 19880-0402, USA.
Chiu
A T
AT
Ellis
C D
CD
Wong
P C
PC
Wexler
R R
RR
Timmermans
P B
PB
D000284:Administration, Oral; D000803:Angiotensin I / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000378:metabolism* / Q000494:pharmacology*; D007093:Imidazoles / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D011945:Receptors, Angiotensin / Q000378:metabolism*; D013329:Structure-Activity Relationship
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D011945:Receptors, Angiotensin; C095055:XR 510; D000803:Angiotensin I