Novel Class of Benzoic Acid Ester Derivatives as Potent PDE4 Inhibitors for Inhaled Administration in the Treatment of Respiratory Diseases

Abstract

The first steps in the selection process of a new anti-inflammatory drug for the inhaled treatment of asthma and chronic obstructive pulmonary disease are herein described. A series of novel ester derivatives of 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloropyridin-4-yl) ethanol have been synthesized and evaluated for inhibitory activity toward cAMP-specific phosphodiesterase-4 (PDE4). In particular, esters of variously substituted benzoic acids were extensively explored, and structural modification of the alcoholic and benzoic moieties were performed to maximize the inhibitory potency. Several compounds with high activity in cell-free and cell-based assays were obtained. Through the evaluation of opportune in vitro ADME properties, a potential candidate suitable for inhaled administration in respiratory diseases was identified and tested in an in vivo model of pulmonary inflammation, proving its efficacy.

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

“…This phenomena may be explained by the previously described very slow dissociation kinetic ( t 1/2  > 20 h) of CHF6001 (compound 32a) (Armani et al. 2014). When we compared a pretreatment of CHF6001 with pretreatment and posttreatment of roflumilast, levels of suppression where not significantly different however, and no treatment reduced cytokine mRNA and protein levels to baseline.…”

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

“…Our study provides an extensive profile of the in vivo efficacy and safety of CHF6001, a novel, extremely potent PDE4 inhibitor (see the companion article, Moretto et al, 2015) specifically developed for topical administration to the airways as a result of an internal discovery and optimization program (Armani et al, 2014).…”

“…wt. 687.54) (Armani et al, 2014), GSK-256066 (6-[3-(dimethylcarbamoyl)phenyl]sulfonyl-4-(3-methoxyanilino)-8-methylquinoline-3-carboxamide; mol. wt.…”

“…Oral administration of CHF6001 did not generate biologically active metabolites (Armani et al, 2014) and resulted in very limited bioavailability (,4%), with plasmatic concentrations orders of magnitude lower than those of roflumilast or its bioactive metabolite roflumilast N-oxide upon administration of similar doses (Bundschuh et al, 2001), therefore limiting the potential systemic exposure associated with swallowing of the drug deposited in the oral cavity during the inhalation process and improving the pulmonary selectivity of the compound.…”

“…This compound has been synthesized as part of a drug discovery project aimed at the identification of compounds endowed with pharmacokinetics and physicochemical properties suitable for inhaled dosing (Armani et al, 2014). The in vitro pharmacologic profile of CHF6001 has been extensively characterized in different cellular assays and is presented in our companion article (Moretto et al, 2015).…”