PHARMACOLOGY OF L-754,142, A HIGHLY POTENT, ORALLY-ACTIVE, NONPEPTIDYL ENDOTHELIN ANTAGONIST

L-754,142, -propylphenoxy)-3,4-methylenedioxyphenylacetamide, is a pot ent nonpeptidyl endothelin antagonist (e.g., K-i: cloned human ET(A) = 0.062 nM; cloned human ET(B) = 2.25 nM), with high specificity for en dothelin receptors. In vitro, L-754,142 is a potent antagonist of ET-1 -induced phosphatidyl inositol hydrolysis in Chinese hamster ovary cel ls expressing cloned human endothelin receptors (IC50: hET(A) = 0.35 n M; hET(B) = 26 nM) and of ET-1 induced contractions in rabbit iliac ar tery rings (pA(2) = 7.74) and rat aortic rings (pA(2) = 8.7). in vivo, L-754,142 is a potent and specific antagonist of exogenously administ ered ET-1 or big ET-1. L-754,142 fully protects against ET-1- induced lethality in mice (AD(50) = 0.26 mg/kg i.v.). The presser response to big ET-1 in the anesthetized ferret is blocked by this compound with a n ED(50) value of 0.019 mg/kg i.v. L-754,142 also blocks the presser r esponse to big ET-1 in the conscious rat with ED(50) values of 0.30 mg /kg i.v, and 0.56 mg/kg p.o. The duration of action of L-754,142 in th is rat model is more than 12 hr after an oral dose of 3 mg/kg. In summ ary, L-754,142 is a potent, orally active ET antagonist with a long du ration of action in several in vivo models.