Endothelin antagonists: discovery of EMD 122946, a highly potent and orally active ETA selective antagonist.
The discovery, in vitro and in vivo studies of the highly potent ETA antagonist EMD 122946 are presented. This compound displayed high binding affinity and functional antagonism [IC50 = 3.2 x 10(-11) M, pA2 = 9.5 (ETA)] and inhibited the ET-1 induced pressor response in pithed rats with an ED50 of 0.3 mg/kg. In conscious spontaneously hypertensive rats and in DOCA-salt hypertensive rats the compound lowered mean blood pressure with an ED50 of 0.06 mg/kg. EMD 122946 exhibited high bioavailability in rats and monkeys.
Mederski
W W
WW
Merck KGaA, Preclinical Pharmaceutical Research, Grafing, Germany. mederski@merck.de
Dorsch
D
D
Osswald
M
M
Anzali
S
S
Christadler
M
M
Schmitges
C J
CJ
Schelling
P
P
Wilm
C
C
Fluck
M
M
D000818:Animals; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D051381:Rats; D044022:Receptor, Endothelin A; D013552:Swine; D013844:Thiazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
C116671:EMD 122946; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D044022:Receptor, Endothelin A; D013844:Thiazoles