RBx 7796: A novel inhibitor of 5-lipoxygenase

Objective: To evaluate the pharmacological profile of RBx 7796, a novel 5-lipoxygenase inhibitor. Materials and methods: RBx 7796 was evaluated for 5- lipoxygenase inhibitory potential using human recombinant enzyme and profiled for selectivity against 12 and 15 lipoxygenase. RBx 7796 was evaluated in cell based assay for inhibition of A23187 induced LTB₄ release from isolated neutrophils. Ex vivo activity was evaluated for inhibition of A23187 induced LTB₄ release in blood from treated rats. In vivo efficacy of RBx 7796 was profiled in LPS induced neutrophilia model in rats and also in ovalbumin induced bronchoconstriction and airway inflammation models in guinea pigs. Results: RBx 7796, a novel chemotype, showed competitive inhibition of 5-lipoxygenase enzyme with an IC₅₀ of 3.5 ± 1.1 μM. RBx 7796 offered >100 fold selectivity against other related enzymes – 12 and 15 lipoxygenase. RBx 7796 inhibited release of LTB₄ from human and rat neutrophils in vitro. Upon administration to rats, RBx 7796 inhibited A23187 induced LTB₄ release from rat neutrophils. Upon repeated administration, dosed once daily, RBx 7796 inhibited LPS induced neutrophil influx in rat airway. RBx 7796 also inhibited allergen induced bronchoconstriction and eosinophil influx in guinea pig airway in a dose dependent manner. Conclusion: The results suggest that RBx 7796, a novel chemotype, is an orally efficacious inhibitor of 5-lipoxygenase enzyme that is effective against both neutrophilic and eosinophilic airway inflammation and shows potent inhibition with once daily administration. Received 9 March 2006; returned for revision 17 May 2006; accepted by I. Ahnfelt-R?nne 19 May 2006