Novel tight-binding inhibitory factor-kappaB kinase (IKK-2) inhibitors demonstrate target-specific anti-inflammatory activities in cellular assays and following oral and local delivery in an in vivo model of airway inflammation.
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.
Sommers
Cynthia D
CD
Department of Inflammation, Pfizer St Louis Laboratories, Chesterfield, Missouri 63017, USA. cynthia.d.sommers@pfizer.com
Thompson
Janice M
JM
Guzova
Julia A
JA
Bonar
Sheri L
SL
Rader
Randall K
RK
Mathialagan
Sumathy
S
Venkatraman
Neetu
N
Holway
Vicky Walker
VW
Kahn
Larry E
LE
Hu
George
G
Garner
Debra S
DS
Huang
Horng-Chih
HC
Chiang
Po-Chang
PC
Schindler
John F
JF
Hu
Yiding
Y
Meyer
Debra M
DM
Kishore
Nandini N
NN
D000284:Administration, Oral; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D018836:Inflammation Mediators / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D008171:Lung Diseases / Q000188:drug therapy / Q000201:enzymology* / Q000276:immunology; D008297:Male; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D051381:Rats
D018836:Inflammation Mediators; D047428:Protein Kinase Inhibitors; D051550:I-kappa B Kinase; C518254:Ikbkb protein, rat