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2‐Substituted indazolinones: orally active and selective 5‐lipoxygenase inhibitors with anti‐inflammatory activity
Author(s) -
Foster S.J.,
Bruneau P.,
Walker E.R.H.,
McMillan R.M.
Publication year - 1990
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1990.tb14663.x
Subject(s) - pharmacology , chemistry , arachidonic acid , potency , arachidonate 5 lipoxygenase , oral administration , lipoxygenase , leukotriene b4 , cyclooxygenase , leukotriene , in vivo , ex vivo , eicosanoid , biochemistry , inflammation , in vitro , enzyme , immunology , medicine , biology , microbiology and biotechnology , asthma
1 This paper describes the pharmacological profile of ICI207968, a novel, orally‐active and selective inhibitor of 5‐lipoxygenase. 2 Inhibition of leukotriene B 4 (LTB 4 ) synthesis by 2‐substituted indazolinones was not directly related to redox potential but was critically dependent on the nature of the N2 substituent. 2‐(3‐Pyridylmethyl)‐indazolinone (ICI207968) combined selectivity and oral potency. 3 In several in vitro systems ICI207968 exhibited similar lipoxygenase inhibitory potency (IC 50 values from 1.5 μ m to 6.0 μ m ) and was approximately 300 times less potent against cyclo‐oxygenase, as measured by inhibition of prostaglandin E 2 (PGE 2 ) synthesis. 4 ICI207968 also produced selective lipoxygenase inhibition following oral administration in the rat. ED 50 values of 2.5, 10 and 25 mg kg −1 p.o. for inhibition of LTB 4 release from A23187‐stimulated blood were obtained 1, 3 and 5 h after dosing. The compound did not inhibit PGE 2 synthesis at oral doses up to 300 mg kg −1 . 5 Co‐administration of ICI207968 with arachidonic acid, into rabbit dermis, potently inhibited both plasma extravasation and polymorphonuclear leucocyte (PMNL) infiltration induced by this inflammatory fatty acid. The anti‐inflammatory potency of a number of intradermally administered indazolinones, with similar redox potentials, was related to their inhibitory potency against leukotriene generation in blood. Oral administration of ICI207968 (100 mg kg −1 ) in the rabbit inhibited ex vivo leukotriene generation in blood and arachidonic acid‐induced skin inflammation. 6 These data demonstrate that ICI207968 is an orally active and selective inhibitor of 5‐lipoxygenase which has anti‐inflammatory properties. ICI207968 will be a valuable agent for clarifying the biological roles of leukotrienes and the therapeutic potential of 5‐lipoxygenase inhibitors.