RT Journal Article
SR Electronic
T1 In vitro pharmacological characterization of CHF6001, a novel selective phosphodiesterase 4 (PDE4) inhibitor with a robust anti-inflammatory profile
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 4860
VO 44
IS Suppl 58
A1 Fabrizio Facchinetti
A1 Nadia Moretto
A1 Paola Caruso
A1 Gessica Marchini
A1 Raffaella Bosco
A1 Chiesa Carnini
A1 Maurizio Civelli
A1 Gino Villetti
YR 2014
UL http://erj.ersjournals.com/content/44/Suppl_58/4860.abstract
AB RationaleBy increasing intracellular cAMP levels, type 4 cyclic nucleotide phosphodiesterases (PDE4) inhibitors elicit a broad spectrum of anti-inflammatory effects. We here compared in vitro CHF6001, a novel PDE4 inhibitor designed for inhaled administration, with two oral (roflumilast and cilomilast) and two inhaled (GSK256066 and UK500,001) PDE4 inhibitors which have all been previously tested in clinical studies.Methods and ResultsCHF6001 was equally potent to GSK256066 and 6- 55- and 923-fold more potent than roflumilast, UK500.001 and cilomilast respectively, in inhibiting PDE4 enzymatic activity (IC50= 0.026±0.006 nM). CHF6001 displayed remarkable anti-inflammatory potencies in several cell-based assays utilizing THP-1 macrophagic cells, human peripheral blood mononuclear cells (PBMC) and eosinophils. In particular, in human THP-1 monocytic-derived macrophages, all the compounds tested inhibited Tumor Necrosis Factor-α (TNF-α) release with the following IC50s: CHF6001, 43 pM; GSK256066, 16 pM; UK 500,001, 3.6 nM ; roflumilast, 4.4 nM, cilomilast, 264 nM. CHF6001 also inhibited the release of TNF-α from PBMC (IC50=28 pM) and the activation of human eosinophils upon fMLP stimulation (IC50=5pM).ConclusionsIn our own drug discovery program we have identified CHF6001, a novel highly potent and selective PDE4 with an in vitro anti-inflammatory potency superior to roflumilast, UK500,001 and cilomilast and comparable to the exceptionally potent GSK256066. CHF6001 has the potential to be an effective topical agent for conditions associated with pulmonary inflammation, including asthma and COPD.