CHF6001 I: A Novel Highly Potent and Selective Phosphodiesterase 4 Inhibitor with Robust Anti-Inflammatory Activity and Suitable for Topical Pulmonary Administration

Abstract

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 (IC 50 5 0.026 6 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 IC 50 values) the release of tumor necrosis factor-a 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-g from CD4 1 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 (ED 50 5 0.205 mmol/kg) and leukocyte infiltration (ED 50 5 0.188 mmol/kg) with an efficacy comparable to a high dose of budesonide (1 mmol/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.

Anti‐inflammatory effects of the novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus‐inducible cytokines

“…2013). CHF6001 is a new inhaled highly specific PDE4 inhibitor that may have improved activity and potency (Moretto et al., 2015; Villetti et al., 2015). …”

“…Furthermore, CHF6001 potently (subnanomolar IC 50 values) inhibited TNF‐ α release from human peripheral blood mononuclear cells and the release of IFN‐ γ from CD4(+) T cells (Moretto et al. 2015). In all these functional assays, CHF6001 was more potent than previously described PDE4 inhibitors, including roflumilast (Moretto et al.…”

“…In all these functional assays, CHF6001 was more potent than previously described PDE4 inhibitors, including roflumilast (Moretto et al. 2015). In summary, the improved potency and implied better efficacy versus roflumilast seen in our studies is in line with other studies.…”

Novel approaches to the management of noneosinophilic asthma

“…High doses of PDE 4 inhibitors may be necessary to treat severe asthma, and gastrointestinal side effects limit their use [Lipworth, 2005;Bateman et al 2006;Bousquet et al 2006]. The inhaled administration of PDE 4 inhibitors may improve the therapeutic index of PDE 4 inhibitors [Chapman et al 2010;Singh et al 2010;Nials et al 2011;De Savi et al 2014;Moretto et al 2015]. Inhaled PDE 4 inhibitors GSK256066 and CHF6001 both inhibit allergeninduced late asthmatic responses [Singh et al 2010;Dave et al 2014] and in patients with moderate COPD, GSK256066 inhaled for 4 weeks was well tolerated although there was no inhibitory effect on sputum and blood inflammatory biomarkers [Watz et al 2013].…”

New and developing non-adrenoreceptor small molecule drugs for the treatment of asthma

“…inhibitors [50][51][52] . Inhaled PDE4 inhibitors GSK256066 and CHF6001 both inhibit allergen-induced late asthmatic responses 53,54 .…”