Design, Synthesis, and Biological Characterization of Inhaled p38?/? MAPK Inhibitors for the Treatment of Lung Inflammatory Diseases

The identification of novel inhaled p38 alpha/beta mitogen-activated protein kinases (MAPK) (MAPK14/11) inhib-itors suitable for the treatment of pulmonary inflammatoryconditions has been described. A rational drug design approachstarted from the identification of a novel tetrahydronaphthaleneseries, characterized by nanomolar inhibition of p38 alpha withselectivity over p38 gamma and p38 delta isoforms. SAR optimization of1cis outlined, where improvements in potency against p38 alpha andligand-enzyme dissociation kinetics led to several compoundsshowing pronounced anti-inflammatory effectsin vitro(inhibitionof TNF alpha release). Targeting of the defined physicochemicalproperties allowed the identification of compounds3h,4e, and4f,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 pulmonaryinflammation. Compound4e, in particular, displayed remarkable efficacy and duration of action and was selected for progression indisease models of asthma and chronic obstructive pulmonary disease (COPD).