Phenylephrine derivatives as leukotriene D4 antagonists.
Two series of phenylephrine derivatives were prepared and tested as inhibitors of leukotriene D4 (LTD4) induced and ovalbumin-induced bronchospasm in the guinea pig. The most potent compound of the urea series, (R)-N,N-diethyl-N-[2-hydroxy-2-[3-(2-quinolinylmethoxy)phenyl]ethyl]-N- methylurea (3, Wy-47,120), was orally active with ED50's of 56 mg/kg vs. LTD4 and 55 mg/kg vs. ovalbumin. When tested as an antagonist of LTD4-induced contraction of isolated guinea pig tracheal strips, 3 was a competitive inhibitor with a p kappa B value of 5.22. In the second series, (R)-3-methyl-5-[3-(2-quinolinylmethoxy)phenyl]-2-oxazolidinone (26, Wy-47,674) had oral ED50's of 36 mg/kg against LTD4 and 95 mg/kg against ovalbumin. Compound 26 selectively antagonized contractile responses of guinea pig trachea evoked by LTD4 (p kappa B = 6.09). In the cat coronary artery, 3 dilated the preparation and blocked the coronary constrictor effect of LTD4. Compound 3 (0.13 mg/kg, iv) also preserved myocardial integrity in rats 48 h after coronary artery ligation. When tested in the rat alcohol-induced gastric lesion model, 3 and 26 manifested a dose-dependent mucosal protection against ethanol.
Musser
J H
JH
Wyeth Laboratories, Philadelphia, Pennsylvania 19101.
Kubrak
D M
DM
Bender
R H
RH
Kreft
A F
AF
Nielsen
S T
ST
Lefer
A M
AM
Chang
J
J
Lewis
A J
AJ
Hand
J M
JM
D000818:Animals; D001986:Bronchial Spasm / Q000188:drug therapy; D002415:Cats; D003326:Coronary Circulation / Q000187:drug effects; D005753:Gastric Mucosa / Q000187:drug effects; D006168:Guinea Pigs; D066298:In Vitro Techniques; D016859:Lipoxygenase Inhibitors; D008297:Male; D010656:Phenylephrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D013189:SRS-A / Q000037:antagonists & inhibitors*; D014132:Trachea / Q000187:drug effects
D016859:Lipoxygenase Inhibitors; D013189:SRS-A; D010656:Phenylephrine