Pharmacology of L-754,142, a highly potent, orally active, nonpeptidyl endothelin antagonist.
L-754,142, (-)-N-(4-iso-propylbenzenesulfonyl)-alpha-(4-carboxyl-2-n-propy lphenoxy)-3,4- methylenedioxyphenylacetamide, is a potent nonpeptidyl endothelin antagonist (e.g., Ki: cloned human ETA = 0.062 nM: cloned human ETB = 2.25 nM), with high specificity for endothelin receptors. In vitro, L-754,142 is a potent antagonist of ET-1-induced phosphatidyl inositol hydrolysis in Chinese hamster ovary cells expressing cloned human endothelin receptors (IC50: hETA = 0.35 nM; hETB = 26 nM) and of ET-1 induced contractions in rabbit iliac artery rings (pA2 = 7.74) and rat aortic rings (pA2 = 8.7). In vivo, L-754,142 is a potent and specific antagonist of exogenously administered ET-1 or big ET-1, L-754,142 fully protects against ET-1-induced lethality in mice (AD50 = 0.26 mg/kg i.v.). The pressor response to big ET-1 in the anesthetized ferret is blocked by this compound with an ED50 value of 0.019 mg/kg i.v. L-754,142 also blocks the pressor response to big ET-1 in the conscious rat with ED50 values of 0.30 mg/kg i.v. and 0.56 mg/kg p.o. The duration of action of L-754,142 in this rat model is more than 12 hr after an oral dose of 3 mg/kg. In summary, L-754,142 is a potent, orally active ET antagonist with a long duration of action in several in vivo models.
Williams
D L
DL
Merck Research Laboratories, West Point, Pennsylvania, USA.
Murphy
K L
KL
Nolan
N A
NA
O'Brien
J A
JA
Pettibone
D J
DJ
Kivlighn
S D
SD
Krause
S M
SM
Lis
E V
EV
Zingaro
G J
GJ
Gabel
R A
RA
D000081:Acetamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors*; D005289:Ferrets; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D010716:Phosphatidylinositols / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000378:metabolism
D000081:Acetamides; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; C097296:L 754142; D010716:Phosphatidylinositols; D017466:Receptors, Endothelin