Structure-activity studies leading to the discovery of 1 (MK-0476) are described. The initial compound of this series, 2, was a potent leukotriene D4 (LTD4) antagonist, but was also a peroxisomal enzyme inducer in the mouse. Structure-activity relationships around the thioether chain were explored to remove this undesirable feature. It was found that alkyl substituents in the ß position relative to the carboxylic acid reduce the potency as a peroxisomal enzyme inducer while preserving the LTD4 antagonistic properties. Dialkyl substitution essentially eliminates the enzyme induction. The optimal styryl quinoline 1 exhibited high in vitro potency and in vivo activity on oral dosing without significant liver enzyme induction in the mouse.

Eicosanoids are important mediators in many physiological and pathophysiological conditions. Sampling the eicosanoids remains a challenge, particularly in the respiratory tract. We examined the possibility that microdialysis might offer a means for sampling the large airways which would provide profiles of local eicosanoid levels before and after challenge. Guinea-pigs were anesthetized by ip injection of urethane and a tracheotomy performed. Microdialysis probes were inserted 2 cm into the tracheal opening, and samples were collected for 1 h intervals over 5 h. Injections of arachidonic acid, leukotriene (LT) D4, or saline vehicle were made iv at the beginning of the third hour. Prostaglandins (PG) E2, D2, F2 alpha and 6-keto-F1 alpha and thromboxane (TX) B2 were determined by GC/MS. Significant post-treatment increases in levels were observed following the injection of arachidonic acid for all eicosanoids except 6-keto-PGF1 alpha. The greatest change was an 8.1-fold increase for PGD2 (P < 0.025) while the smallest change was a 3.5-fold increase for TXB2 (P < 0.025). Intravenous administration of LTD4 caused significant increases in levels of PGE2 (P < 0.025), PGF2 alpha (P < 0.05) and 6-keto-PGF1 alpha (P < 0.025) in the first hour after challenge. No increase was observed in control experiments following saline injection. These results indicate that microdialysis provides a useful methodology for sampling local eicosanoid production.