RBx 7,796: A novel inhibitor of 5-lipoxygenase.
OBJECTIVE
To evaluate the pharmacological profile of RBx 7,796, a novel 5-lipoxygenase inhibitor.


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.


CONCLUSIONS
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.
Shirumalla
R K
RK
Department of Pharmacology, New Drug Discovery Research, Ranbaxy Research Laboratories, Plot No-20, Sector-18, Udyog Vihar, Gurgaon, Haryana 122015, India.
Naruganahalli
K S
KS
Dastidar
S G
SG
Sattigeri
V
V
Kaur
G
G
Deb
C
C
Gupta
J B
JB
Salman
M
M
Ray
A
A
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase; D016084:Bronchoconstriction; D004804:Eosinophils / Q000187:drug effects; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects
D016859:Lipoxygenase Inhibitors; D001094:Arachidonate 5-Lipoxygenase