PMID: 8614266Jan 1, 1996Paper

Pharmacology of L-744,453, a novel nonpeptidyl endothelin antagonist

Life Sciences
D L WilliamsW J Greenlee

Abstract

L-744,453 ((+/-)3-[4-(1-carboxy-1-(3,4-methylenedioxyphenyl)methoxy)-3,5-diprop ylphenyl methyl]-3H-imidazo[4,5-c]pyridine) is an endothelin (ET) receptor antagonist from a new structural class, the dipropyl-alpha-phenoxyphenylacetic acid derivatives. L-744,453 competitively and reversibly inhibits [125I]-ET-1 binding to Chinese Hamster Ovary cells expressing cloned human ET receptors (K(i)s: hET(A)=4.3 nM; hET(B)=232 nM), and is selective for endothelin receptors compared to other peptide receptors. It is an antagonist of ET-1 stimulated phosphatidyl inositol hydrolysis in rat uterine slices (IC50=220 nM) and exhibits no agonist activity. This compound also inhibits ET-1 stimulated contraction of rat aortic rings with a K(b) value of 50 nM. L-744,453 protects against ET-1 induced lethality in mice after i.v. (AD50=13 mg/kg i.v.) or oral administration. This compound also antagonizes ET-1 induced increases in diastolic blood pressure in conscious normotensive rats (AD50=0.67 mg/kg i.v.) and anesthetized ferrets (AD50=1.6 mg/kg i.v.). L-744,453 is a potent, selective, orally active endothelin antagonist which may be useful in elucidating the role of endothelin in normal and pathophysiological states.

References

Apr 15, 1992·Biochemical and Biophysical Research Communications·J F HessR W Ransom
Oct 1, 1992·Trends in Pharmacological Sciences·S S Stojilković, K J Catt
Jul 1, 1992·Medicinal Research Reviews·T MasakiK Goto
Nov 10, 1991·Biochemical and Biophysical Research Communications·D L WilliamsR F Nutt
Aug 16, 1994·Proceedings of the National Academy of Sciences of the United States of America·E H OhlsteinJ S Frazee
Jan 1, 1993·Life Sciences·D L WilliamsJ S Tung
Mar 1, 1993·Peptides·B BattistiniP Sirois

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Citations

Sep 24, 2002·Pharmacology & Therapeutics·P D'Orléans-JusteJ C Honoré
Dec 10, 2003·Expert Opinion on Emerging Drugs·Prabal K Chatterjee, Christoph Thiemermann

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