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

British Journal of Pharmacology
S J FosterR M McMillan

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 microM to 6.0 microM) 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...Continue Reading

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Citations

Aug 2, 2000·Pediatric Pulmonology·H Bisgaard
Sep 1, 1991·Agents and Actions·K E Proudman, R M McMillan
Aug 1, 1992·Trends in Pharmacological Sciences·R M McMillan, E R Walker
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Jan 5, 1999·Bioorganic & Medicinal Chemistry Letters·B CharpiotT Mueller

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