RT Journal Article
SR Electronic
T1 CHF6001 II: A Novel Phosphodiesterase 4 Inhibitor, Suitable for Topical Pulmonary Administration—In Vivo Preclinical Pharmacology Profile Defines a Potent Anti-Inflammatory Compound with a Wide Therapeutic Window
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 568
OP 578
DO 10.1124/jpet.114.220558
VO 352
IS 3
A1 Gino Villetti
A1 Chiara Carnini
A1 Loredana Battipaglia
A1 Laurent Preynat
A1 Pier Tonino Bolzoni
A1 Franco Bassani
A1 Paola Caruso
A1 Marco Bergamaschi
A1 Anna Rita Pisano
A1 Veronica Puviani
A1 Fabio Franco Stellari
A1 Valentina Cenacchi
A1 Roberta Volta
A1 Vittorio Bertacche
A1 Valentina Mileo
A1 Valentina Bagnacani
A1 Elisa Moretti
A1 Paola Puccini
A1 Silvia Catinella
A1 Fabrizio Facchinetti
A1 Angelo Sala
A1 Maurizio Civelli
YR 2015
UL http://jpet.aspetjournals.org/content/352/3/568.abstract
AB 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.