{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T23:47:47Z","timestamp":1791157667927,"version":"4.1.0"},"reference-count":0,"publisher":"Canadian Science Publishing","issue":"5","license":[{"start":{"date-parts":[[1989,5,1]],"date-time":"1989-05-01T00:00:00Z","timestamp":609984000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/www.nrcresearchpress.com\/page\/about\/CorporateTextAndDataMining"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Can. J. Physiol. Pharmacol."],"published-print":{"date-parts":[[1989,5,1]]},"abstract":"<jats:p> L-663,536 (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid) is a potent inhibitor of leukotriene (LT) biosynthesis in intact human polymorphonuclear leukocytes (PMN) (IC<jats:sub>50<\/jats:sub>, 2.5\u2002nM). Similarly, L-663,536 inhibited A23187-induced LTB<jats:sub>4<\/jats:sub> formation by rat peripheral blood and elicited PMN. At concentrations where inhibition of leukotriene biosynthesis occurred in human whole blood (1.1\u2002\u03bcM), no effect was seen on cyclooxygenase or 12-lipoxygenase, an effect also observed in washed human platelets. The compound had no effect on rat or porcine 5-lipoxygenase indicating that L-663,536 is not a direct 5-lipoxygenase inhibitor. When administered in vivo L-663,536 was a potent inhibitor of antigen-induced dyspnea in inbred rats pretreated with methysergide (ED<jats:sub>50<\/jats:sub>, 0.036\u2002mg\/kg\u2002p.o.) and of Ascaris-induced bronchoconstriction in squirrel monkeys (1\u2002mg\/kg\u2002p.o.). The compound inhibited leukotriene biosynthesis in vivo in a rat pleurisy model (ED<jats:sub>50<\/jats:sub>, 0.2\u2002mg\/kg\u2002p.o.), an inflamed rat paw model (ED<jats:sub>50<\/jats:sub>, 0.8\u2002mg\/kg), a model of leukotriene excretion in rat bile following antigen provocation, and a model in the guinea-pig ear where leukotriene synthesis was induced by topical challenge with ionophore A23187 (ED<jats:sub>50<\/jats:sub>, 2.5\u2002mg\/kg\u2002p.o. and 0.6\u2002\u03bcg topically). The results indicate that L-663,536 is a potent inhibitor of leukotriene biosynthesis both in vitro and in vivo indicating that the compound is suitable for studying the role of leukotrienes in a variety of pathological situations.Key words: leukotriene, 5-lipoxygenase, polymorphonuclear leukocytes, leukotriene B<jats:sub>4<\/jats:sub>, leukotriene inhibitor. <\/jats:p>","DOI":"10.1139\/y89-073","type":"journal-article","created":{"date-parts":[[2011,4,24]],"date-time":"2011-04-24T04:56:31Z","timestamp":1303620991000},"page":"456-464","source":"Crossref","is-referenced-by-count":272,"title":["L-663,536 (MK-886) (3-[1-(4-chlorobenzyl)-3-<i>t<\/i>-butyl-thio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid), a novel, orally active leukotriene biosynthesis inhibitor"],"prefix":"10.1139","volume":"67","author":[{"given":"J.","family":"Gillard","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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