TY - JOUR T1 - CHF6001 I: A Novel Highly Potent and Selective Phosphodiesterase 4 Inhibitor with Robust Anti-Inflammatory Activity and Suitable for Topical Pulmonary Administration JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 559 LP - 567 DO - 10.1124/jpet.114.220541 VL - 352 IS - 3 AU - Nadia Moretto AU - Paola Caruso AU - Raffaella Bosco AU - Gessica Marchini AU - Fiorella Pastore AU - Elisabetta Armani AU - Gabriele Amari AU - Andrea Rizzi AU - Eleonora Ghidini AU - Renato De Fanti AU - Carmelida Capaldi AU - Laura Carzaniga AU - Emilio Hirsch AU - Carola Buccellati AU - Angelo Sala AU - Chiara Carnini AU - Riccardo Patacchini AU - Maurizio Delcanale AU - Maurizio Civelli AU - Gino Villetti AU - Fabrizio Facchinetti Y1 - 2015/03/01 UR - http://jpet.aspetjournals.org/content/352/3/559.abstract N2 - This study examined the pharmacologic characterization of CHF6001 [(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzoyloxy)ethyl)pyridine 1-oxide], a novel phosphodiesterase (PDE)4 inhibitor designed for treating pulmonary inflammatory diseases via inhaled administration. CHF6001 was 7- and 923-fold more potent than roflumilast and cilomilast, respectively, in inhibiting PDE4 enzymatic activity (IC50 = 0.026 ± 0.006 nM). CHF6001 inhibited PDE4 isoforms A–D with equal potency, showed an elevated ratio of high-affinity rolipram binding site versus low-affinity rolipram binding site (i.e., >40) and displayed >20,000-fold selectivity versus PDE4 compared with a panel of PDEs. CHF6001 effectively inhibited (subnanomolar IC50 values) the release of tumor necrosis factor-α from human peripheral blood mononuclear cells, human acute monocytic leukemia cell line macrophages (THP-1), and rodent macrophages (RAW264.7 and NR8383). Moreover, CHF6001 potently inhibited the activation of oxidative burst in neutrophils and eosinophils, neutrophil chemotaxis, and the release of interferon-γ from CD4+ T cells. In all these functional assays, CHF6001 was more potent than previously described PDE4 inhibitors, including roflumilast, UK-500,001 [2-(3,4-difluorophenoxy)-5-fluoro-N-((1S,4S)-4-(2-hydroxy-5-methylbenzamido)cyclohexyl)nicotinamide], and cilomilast, and it was comparable to GSK256066 [6-((3-(dimethylcarbamoyl)phenyl)sulfonyl)-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide]. When administered intratracheally to rats as a micronized dry powder, CHF6001 inhibited liposaccharide-induced pulmonary neutrophilia (ED50 = 0.205 μmol/kg) and leukocyte infiltration (ED50 = 0.188 μmol/kg) with an efficacy comparable to a high dose of budesonide (1 μmol/kg i.p.). In sum, CHF6001 has the potential to be an effective topical treatment of conditions associated with pulmonary inflammation, including asthma and chronic obstructive pulmonary disease. ER -