Discovery of (2-Fluoro-Benzyl)-(2-Methyl-2-Phenethyl-2H-Chromen-6-yl)-Amine (KRH-102140) as an Orally Active 5-Lipoxygenase Inhibitor with Activity in Murine Inflammation Models

Abstract

Objective and Design: We investigated anti-inflammatory properties of a novel 5-lipoxygenase (5-LO) inhibitor, KRH-102140, in vitro and in vivo. 5-LO enzyme activity was assayed using insect cell lysates overexpressing rat 5-LO. The leukotriene B₄ (LTB₄) level was assayed in rat basophilic leukemia (RBL-1) cell line. ICR (Institute of Cancer Research) mice were used for in vivo assays. Mouse ear edema was induced by topical application of arachidonic acid. An air pouch was induced by subcutaneous injection of sterile air into mice, followed by zymosan treatment. Sprague-Dawley rats were used for pharmacokinetic studies. Results: KRH-102140 inhibited 5-LO activity with an IC₅₀ value of 160 ± 23 nmol/l in parallel with LTB₄ inhibition in RBL-1 cells. Oral administration of KRH-102140 (10–100 mg/kg) reduced ear edema, myeloperoxidase activity and LTB₄ production in murine inflammation models. Oral bioavailability as determined in rats was 66%. Conclusions: Our results show that KRH-102140, a new 5-LO inhibitor, exhibits potent anti-inflammatory activities in vitro as well as in vivo.