title: Endothelin antagonists: discovery of EMD 122946, a highly potent and orally active ETA selective antagonist.
abstract: 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.
authors.affiliation: Merck KGaA, Preclinical Pharmaceutical Research, Grafing, Germany. mederski@merck.de
authors.forename: W W
authors.initials: WW
authors.lastname: Mederski
authors.forename: D
authors.initials: D
authors.lastname: Dorsch
authors.forename: M
authors.initials: M
authors.lastname: Osswald
authors.forename: S
authors.initials: S
authors.lastname: Anzali
authors.forename: M
authors.initials: M
authors.lastname: Christadler
authors.forename: C J
authors.initials: CJ
authors.lastname: Schmitges
authors.forename: P
authors.initials: P
authors.lastname: Schelling
authors.forename: C
authors.initials: C
authors.lastname: Wilm
authors.forename: M
authors.initials: M
authors.lastname: Fluck
mesh_terms: 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*
chemical_list: C116671:EMD 122946; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D044022:Receptor, Endothelin A; D013844:Thiazoles