RESUMO
OBJECTIVE: RBx 7796, a 5-lipoxygenase inhibitor, was evaluated in in vivo efficacy models, in vitro ADME and in vivo pharmacokinetic models. METHOD: RBx 7796 was evaluated for inhibition of 5-lipoxygenase enzyme and release of LTB4 from isolated rat and human neutrophils. RBx 7796 was tested in allergic bronchoconstriction model in Balb/c mice and LPS induced airway hyperreactivity model in rats. RBx 7796 was evaluated for metabolic stability in liver microsomes and cytochrome P450 inhibition potential. Pharmacokinetic profile of RBx 7796 was also determined in rat and dog. RESULTS: RBx 7796 inhibited 5-lipoxygenase enzyme and inhibited release of LTB4 from neutrophils. RBx 7796 also inhibited early and late airway reactivity following allergen challenge in mouse model. LPS induced increase in airway reactivity was blocked by RBx 7796. Compound was found to be stable in liver microsomes and devoid of major cytochrome P450 inhibition potential. The oral bioavailability of RBx 7796 in rat and dog was 83 % and 47 %, respectively. Following repeated daily administration, compound did not exhibit any sign of accumulation and/or tendency to induce its own metabolism. CONCLUSION: The results suggest that RBx 7796 is an inhibitor of 5-lipoxygenase enzyme that is orally efficacious in two different models of airway reactivity. The molecule also demonstrated acceptable pharmacokinetic profile warranting further development.
Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Hidroxiureia/análogos & derivados , Inibidores de Lipoxigenase/farmacologia , Inibidores de Lipoxigenase/farmacocinética , Animais , Hiper-Reatividade Brônquica/imunologia , Calcimicina/metabolismo , Cães , Humanos , Hidroxiureia/administração & dosagem , Hidroxiureia/química , Hidroxiureia/farmacocinética , Hidroxiureia/farmacologia , Ionóforos/metabolismo , Leucotrieno B4/metabolismo , Lipopolissacarídeos/imunologia , Inibidores de Lipoxigenase/administração & dosagem , Inibidores de Lipoxigenase/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Ratos , Ratos Wistar , Sais/químicaRESUMO
OBJECTIVE: To evaluate the pharmacological profile of RBx 7,796, a novel 5-lipoxygenase inhibitor. MATERIALS AND METHODS: RBx 7,796 was evaluated for 5- lipoxygenase inhibitory potential using human recombinant enzyme and profiled for selectivity against 12 and 15 lipoxygenase. RBx 7,796 was evaluated in cell based assay for inhibition of A23,187 induced LTB(4) release from isolated neutrophils. Ex vivo activity was evaluated for inhibition of A23,187 induced LTB(4) release in blood from treated rats. In vivo efficacy of RBx 7,796 was profiled in LPS induced neutrophilia model in rats and also in ovalbumin induced bronchoconstriction and airway inflammation models in guinea pigs. RESULTS: RBx 7,796, a novel chemotype, showed competitive inhibition of 5-lipoxygenase enzyme with an IC(50) of 3.5 +/- 1.1 microM. RBx 7,796 offered >100 fold selectivity against other related enzymes - 12 and 15 lipoxygenase. RBx 7,796 inhibited release of LTB(4) from human and rat neutrophils in vitro. Upon administration to rats, RBx 7,796 inhibited A23,187 induced LTB(4) release from rat neutrophils. Upon repeated administration, dosed once daily, RBx 7,796 inhibited LPS induced neutrophil influx in rat airway. RBx 7,796 also inhibited allergen induced bronchoconstriction and eosinophil influx in guinea pig airway in a dose dependent manner. CONCLUSION: The results suggest that RBx 7,796, 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.
