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.

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 / G. Villetti, C. Carnini, L. Battipaglia, L. Preynat, P.T. Bolzoni, F. Bassani, P. Caruso, M. Bergamaschi, A.R. Pisano, V. Puviani, F.F. Stellari, V. Cenacchi, R. Volta, V. Bertacche, V. Mileo, V. Bagnacani, E. Moretti, P. Puccini, S. Catinella, F. Facchinetti, A. Sala, M. Civelli. - In: JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS. - ISSN 0022-3565. - 352:3(2015 Mar), pp. 568-578. [10.1124/jpet.114.220558]

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

A. Sala
Penultimo
;
2015

Abstract

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.
Pharmacology; Molecular Medicine
Settore BIO/14 - Farmacologia
mar-2015
Article (author)
File in questo prodotto:
File Dimensione Formato  
J Pharmacol Exp Ther-2015-Villetti-568-78.pdf

accesso riservato

Tipologia: Publisher's version/PDF
Dimensione 1.15 MB
Formato Adobe PDF
1.15 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/268861
Citazioni
  • ???jsp.display-item.citation.pmc??? 18
  • Scopus 40
  • ???jsp.display-item.citation.isi??? 40
social impact