{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T05:06:32Z","timestamp":1741237592755,"version":"3.38.0"},"reference-count":36,"publisher":"Wiley","issue":"2b","license":[{"start":{"date-parts":[[2011,8,28]],"date-time":"2011-08-28T00:00:00Z","timestamp":1314489600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2011,9,2]]},"abstract":"<jats:p><jats:bold>BACKGROUND AND PURPOSE<\/jats:bold>5\u2010Lipoxygenase (5\u2010LO) is the key enzyme in the biosynthesis of pro\u2010inflammatory leukotrienes (LTs) representing a potential target for pharmacological intervention with inflammation and allergic disorders. Although many LT synthesis inhibitors are effective in simple<jats:italic>in vitro<\/jats:italic>test systems, they frequently fail<jats:italic>in vivo<\/jats:italic>due to lack of efficacy. Here, we attempted to assess the pharmacological potential of the previously identified 5\u2010LO inhibitor 2\u2010(4\u2010(biphenyl\u20104\u2010ylamino)\u20106\u2010chloropyrimidin\u20102\u2010ylthio)octanoic acid (HZ52).<\/jats:p><jats:p><jats:bold>EXPERIMENTAL APPROACH<\/jats:bold>We evaluated the efficacy of HZ52<jats:italic>in vivo<\/jats:italic>using carrageenan\u2010induced pleurisy in rats and platelet\u2010activating factor (PAF)\u2010induced lethal shock in mice. We also characterized 5\u2010LO inhibition by HZ52 at the cellular and molecular level in comparison with other types of 5\u2010LO inhibitor, that is, BWA4C, ZM230487 and hyperforin.<\/jats:p><jats:p><jats:bold>KEY RESULTS<\/jats:bold>HZ52, 1.5\u2003mg\u00b7kg<jats:sup>\u22121<\/jats:sup>i.p., prevented carrageenan\u2010induced pleurisy accompanied by reduced LTB<jats:sub>4<\/jats:sub>levels and protected mice (10\u2003mg\u00b7kg<jats:sup>\u22121<\/jats:sup>, i.p.) against PAF\u2010induced shock. Detailed analysis in cell\u2010based and cell\u2010free assays revealed that inhibition of 5\u2010LO by HZ52 (i) does not depend on radical scavenging properties and is reversible; (ii) is not impaired by an increased peroxide tone or by elevated substrate concentrations; and (iii) is little affected by the cell stimulus or by phospholipids, glycerides, membranes or Ca<jats:sup>2+<\/jats:sup>.<\/jats:p><jats:p><jats:bold>CONCLUSIONS AND IMPLICATIONS<\/jats:bold>HZ52 is a promising new type of 5\u2010LO inhibitor with efficacy<jats:italic>in vivo<\/jats:italic>and with a favourable pharmacological profile. It possesses a unique 5\u2010LO inhibitory mechanism different from classical 5\u2010LO inhibitors and seemingly lacks the typical disadvantages of former classes of LT synthesis blockers.<\/jats:p>","DOI":"10.1111\/j.1476-5381.2011.01451.x","type":"journal-article","created":{"date-parts":[[2011,4,21]],"date-time":"2011-04-21T07:19:01Z","timestamp":1303370341000},"page":"781-793","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["2\u2010(4\u2010(Biphenyl\u20104\u2010ylamino)\u20106\u2010chloropyrimidin\u20102\u2010ylthio)octanoic acid (HZ52) \u2013 a novel type of 5\u2010lipoxygenase inhibitor with favourable molecular pharmacology and efficacy<i>in 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