Pulmonary-Allergy, Dermatological, Gastrointestinal & Arthritis: 5-Lipoxygenase inhibitors

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)