Abstract
This series of Zeneca patents discloses inhibitors of 5-lipoxygenase, (5-LO) which are useful in the treatment of various leukotriene-mediated inflammatory and/or allergic conditions.
Vinyl esters are disclosed in EP-581464 [101], pyrrolid-ines in EP-586229 [102], acetanilides in EP-610032 [101] and oxiones in WO9417054 [104].
In the first patent inhibition of 5-LO was determined in vitro by measuring LTB4 biosynthesis inhibition in Ca2+ ionophore-challenged human whole blood. The synthesis of five examples are described in detail. Specific in vitro data is given for three compounds, with IC50 values ranging from 0.07–9.36 μM. Among the four compounds specifically claimed is naphth-2-ylmethyl-(Z)-3-amino-3-(4-niethoxytetrahydropyran-4-yl)prop-2-enoate (1C50=0.07 μM)
Results are given for five of the pyrrolidine compounds disclosed in [102] and these show good LTB4 inhibition (IC50s = 0.03–0.21 μM). The specified compound has an IC50 value of 0.04 μM against LTB4 and an ED50 value of approximately 0.5mg/kg versus LTB4 in the in vivo zymosan-induced LTB4 model. Eight compounds are specifically claimed including the specified compound, 3-(5-fluro-3-(4-(1-hydroxyimioethyl) phenylthio)phenyl)-3-methoxy-1-(2,2,2-trifluoroethyl) pyrrolidine (2).
Four test models are briefly described for the compounds disclosed in [102]. Inhibition of LTB4 (and TXB2) production in human whole blood, induced by A23187, was determined by RIA as desdbed by Carey & Forder. The specified compound had an IC50 of 0.04 mM in vitro.
An in vitro heparinised blood/clacium ionophore test was used for the oximes in [104] IC50 values (LTE50 were 0.01–40 μM. Detailed methods are provided for the synthesis of oxime derivatives. Ten compounds are specifically claimed, including (E) 4′-(5-fluoro-3-((2S,4R)-4-hydroxy-2-methyltetrahydropyran-4-yl)phe nylthio)acetophenone oxime (4)