Design, Synthesis, and Biological Characterization of Inhaled p38α/β MAPK Inhibitors for the Treatment of Lung Inflammatory Diseases

The
identification of novel inhaled p38α/β mitogen-activated
protein kinases (MAPK) (MAPK14/11) inhibitors suitable for the treatment
of pulmonary inflammatory conditions has been described. A rational
drug design approach started from the identification of a novel tetrahydronaphthalene
series, characterized by nanomolar inhibition of p38α with selectivity
over p38γ and p38δ isoforms. SAR optimization of 1c is outlined, where improvements in potency against p38α
and ligand–enzyme dissociation kinetics led to several compounds
showing pronounced anti-inflammatory effects in vitro (inhibition of TNFα release). Targeting of the defined physicochemical
properties allowed the identification of compounds 3h, 4e, and 4f, which showed, upon intratracheal
instillation, low plasma levels, prolonged lung retention, and anti-inflammatory
effects in a rat acute model of a bacterial endotoxin-induced pulmonary
inflammation. Compound 4e, in particular, displayed remarkable
efficacy and duration of action and was selected for progression in
disease models of asthma and chronic obstructive pulmonary disease
(COPD).