Pharmacologic actions of the second generation leukotriene B4 receptor antagonist LY29311: in vivo pulmonary studies.
We examined the in vivo actions of LY293111 sodium (2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]pro poxy]phenoxy] benzoic acid sodium salt). Guinea pigs were used to evaluate the effect of this agent on (1) acute airway obstruction produced by intravenous leukotriene B4, (2) pulmonary granulocyte infiltration and delayed onset airway obstruction resulting from a 4-h leukotriene B4 inhalation and (3) lung inflammation after aerosol challenge with the divalent cationic ionophore A23187 (6S-[6alpha(2S*,3S*),8beta(R*),9beta,11alpha]-5- (methylamino)-2-[[3,9,11-trimethyl-8-[1-methyl-2-oxo-2-(1H-pyrrol-2-yl)e thyl]-1,7-dioxaspiro[5.5]undec-2-yl]methyl]-4-benzoxazole carboxylic acid). Airway obstruction was quantitated using pulmonary gas trapping measurements and lung inflammation was evaluated by bronchoalveolar lavage (BAL) and histology. LY293111 sodium produced a dose-related inhibition of acute leukotriene B4-induced airway obstruction when administered i.v. (ED50=14 microg/kg) or p.o. (ED50=0.4 mg/kg). In contrast, LY293111 sodium did not inhibit the pulmonary gas trapping caused by aerosols of histamine, leukotriene D4, or the thromboxane mimetic U46619 (15 [(S)-hydroxy11a,9a-(epoxymethano)prosta-5Z,13E-dienoic acid]). Oral LY293111 sodium inhibited leukotriene B4-induced bronchoalveolar lavage granulocyte infiltration and delayed onset airway obstruction at doses as low as 0.3 mg/kg. In A23187-challenged animals, pulmonary inflammation was markedly inhibited at 1 h, but not 2 h and 4 h post-exposure. We conclude that LY293 11 sodium is a selective leukotriene B4 receptor antagonist with potent pulmonary anti-inflammatory activity.
Silbaugh
S A
SA
Eli Lilly and Company, Lilly Research Laboratories, Greenfield Laboratories, Indiana 46140, USA. silbaugh_steven_a@lilly.com
Stengel
P W
PW
Cockerham
S L
SL
Froelich
L L
LL
Bendele
A M
AM
Spaethe
S M
SM
Sofia
M J
MJ
Sawyer
J S
JS
Jackson
W T
WT
D000402:Airway Obstruction / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D000001:Calcimycin; D002634:Chemotaxis, Leukocyte; D015232:Dinoprostone / Q000096:biosynthesis / Q000097:blood; D006098:Granulocytes / Q000473:pathology; D006168:Guinea Pigs; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000097:blood; D008168:Lung / Q000473:pathology; D008297:Male; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors*; D013929:Thromboxane B2 / Q000096:biosynthesis / Q000097:blood
D001565:Benzoates; D001578:Benzopyrans; C094099:LY 293111; D020024:Leukotriene Antagonists; D018102:Receptors, Leukotriene B4; C059950:SC 41930; D007975:Leukotriene B4; D000001:Calcimycin; D013929:Thromboxane B2; D015232:Dinoprostone