Pharmacology of L-744,453, a novel nonpeptidyl endothelin antagonist.
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.
Williams
D L
DL
Department of New Lead Pharmacology, Merck Research Laboratories, West Point, PA 19486, USA.
Murphy
K L
KL
Nolan
N A
NA
O'Brien
J A
JA
Lis
E V
EV
Pettibone
D J
DJ
Clineschmidt
B V
BV
Krause
S M
SM
Veber
D F
DF
Naylor
E M
EM
Chakravarty
P K
PK
Walsh
T F
TF
Dhanoa
D M
DM
Chen
A
A
Bagley
S W
SW
Fitch
K J
KJ
Greenlee
W J
WJ
D000818:Animals; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D004149:Dioxoles / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D005289:Ferrets; D006801:Humans; D006868:Hydrolysis; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D007700:Kinetics; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000378:metabolism; D013329:Structure-Activity Relationship
D004149:Dioxoles; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007093:Imidazoles; D007457:Iodine Radioisotopes; C099174:L 744453; D010716:Phosphatidylinositols; D017466:Receptors, Endothelin