2-Substituted indazolinones: orally active and selective 5-lipoxygenase inhibitors with anti-inflammatory activity

Abstract

1 This paper describes the pharmacological profile of ICI207968, a novel, orally-active and selective inhibitor of 5-lipoxygenase. 2 Inhibition of leukotriene B₄ (LTB₄) 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 (IC₅₀ values from 1.5 μm to 6.0 μm) and was approximately 300 times less potent against cyclo-oxygenase, as measured by inhibition of prostaglandin E₂ (PGE₂) synthesis. 4 ICI207968 also produced selective lipoxygenase inhibition following oral administration in the rat. ED₅₀ values of 2.5, 10 and 25 mg kg⁻¹ p.o. for inhibition of LTB₄ release from A23187-stimulated blood were obtained 1, 3 and 5 h after dosing. The compound did not inhibit PGE₂ 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.