CHF6001 [(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzoyloxy)ethyl)
pyridine 1-
oxide] is a novel
phosphodiesterase 4 (
PDE4) inhibitor designed for use in
pulmonary diseases by inhaled administration. Intratracheal administration of
CHF6001 to
ovalbumin-sensitized Brown-Norway rats suppressed the
antigen-induced decline of lung functions (ED50 = 0.1 µmol/kg) and
antigen-induced
eosinophilia (ED50 = 0.03 µmol/kg) when administered (0.09 μmol/kg) up to 24 hours before
antigen challenge, in agreement with CHF6001-sustained lung concentrations up to 72 hours after intratracheal treatment (mean residence time 26 hours). Intranasal, once daily administration of
CHF6001 inhibited neutrophil infiltration observed after 11 days of tobacco
smoke exposure in mice, both upon prophylactic (0.15-0.45 µmol/kg per day) or interventional (0.045-0.45 µmol/kg per day) treatment.
CHF6001 was ineffective in reversing
ketamine/
xylazine-induced
anesthesia (a surrogate of
emesis in rat) up to 5 µmol/kg administered intratracheally, a dose 50- to 150-fold higher than anti-inflammatory ED50 observed in rats. When given topically to ferrets, no
emesis and
nausea were evident up to 10 to 20 µmol/kg, respectively, whereas the
PDE4 inhibitor GSK-256066 (6-[3-(dimethylcarbamoyl)phenyl]sulfonyl-4-(3-methoxyanilino)-8-methylquinoline-3-carboxamide) induced
nausea at 1 µmol/kg intratracheally. A 14-day inhalation toxicology study in rats showed a no-observed-adverse-effect level dose of 4.4 µmol/kg per day for
CHF6001, lower than the 0.015 μmol/kg per day for
GSK-256066.
CHF6001 was found effective and extremely well tolerated upon
topical administration in relevant animal models, and may represent a step forward in PDE4 inhibition for the treatment of
asthma and chronic obstructive respiratory disease.