Nuclear factor-kappaB (
NF-kappaB) is one of the major families of
transcription factors activated during the inflammatory response in
asthma and
chronic obstructive pulmonary disease. Inhibitory factor-kappaB
kinase 2 (IKK-2) has been shown to play a pivotal role in
cytokine-induced
NF-kappaB activation in airway epithelium and in disease-relevant cells. Nevertheless, the potential toxicity of specific IKK-2 inhibitors may be unacceptable for oral delivery in
chronic obstructive pulmonary disease. Therefore, local delivery to the lungs is an attractive alternative that warrants further exploration. Here, we describe potent and selective small-molecule IKK-2 inhibitors [8-(5-chloro-2-(4-methylpiperazin-1-yl)isonicotinamido)-1-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]
indazole-3-carboxamide (PHA-408) and 8-(2-(3,4-bis(hydroxymethyl)-3,4-dimethylpyrrolidin-1-yl)-5-chloroisonicotinamido)-1-(4-fluorophenyl)-4,5-dihydro-1H-benzo-[g]
indazole-3-carboxamide (PF-184)] that are competitive for
ATP have slow off-rates from IKK-2 and display broad in vitro anti-inflammatory activities resulting from
NF-kappaB pathway inhibition. Notably, PF-184 has been designed to have high systemic clearance, which limits systemic exposure and maximizes the effects locally in the airways. We used an inhaled
lipopolysaccharide-induced rat model of neutrophilia to address whether inhibiting
NF-kappaB activation locally within the airways would show anti-inflammatory effects in the absence of systemic exposure.
PHA-408, a low-clearance compound previously shown to be efficacious orally in a rodent model of
arthritis, dose-dependently attenuated inhaled
lipopolysaccharide-induced cell infiltration and
cytokine production. Interestingly, PF-184 produced comparable dose-dependent anti-inflammatory activity by intratracheal administration and was as efficacious as intratracheally administered
fluticasone propionate (
fluticasone). Together, these results support the potential therapeutic utility of IKK-2 inhibition in inflammatory
pulmonary diseases and demonstrate anti-inflammatory efficacy of an inhaled IKK-2 inhibitor in a rat airway model of neutrophilia.