Pharmacologic characterization of the novel, orally available endothelin-A--selective antagonist SB 247083.
Competition radioligand binding with [125I]ET-1 at human cloned ETA and ETB receptors demonstrated ET-A selective affinity by SB 247083 (Ki 0.41 and 467 nM, respectively). Accordingly, similar competitive, functional ETA receptor antagonism was observed. In vitro, SB 247083 exhibited a Kb of 3.5 +/- 0.3 nM (ET-1--induced rat aortic contraction). SB 247083 was significantly less potent as a functional ETB antagonist (Kb 0.34 +/- 0.01 microM; S6c-induced rabbit pulmonary artery contraction). In contrast to ETB-selective and mixed ETA/B antagonists, and consistent with its ETA-selective profile, in vivo administration of SB 247083 was not associated with an elevation in plasma ET-1 levels. Pharmacodynamic and pharmacokinetic studies revealed that SB 247083 was effectively absorbed from the gastrointestinal tract. A single bolus dose inhibited the hemodynamic actions of ET-1 for up to 8 h, consistent with a molecule shown to be 46% bioavailable. Therefore, the present study demonstrates that SB 247083, a unique chemical entity, represents a potent class of nonpeptide, orally active ETA-selective antagonists.
Douglas
S A
SA
Department of Cardiovascular, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939, USA.
Nambi
P
P
Gellai
M
M
Luengo
J I
JI
Xiang
J N
JN
Brooks
D P
DP
Ruffolo
R R
RR
Elliott
J D
JD
Ohlstein
E H
EH
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001572:Benzofurans / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D006801:Humans; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011422:Propionates / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
D001572:Benzofurans; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011422:Propionates; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C113045:SB 247083; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6