Design, Synthesis, and Biological Characterization of Inhaled p38α/β MAPK Inhibitors for the Treatment of Lung Inflammatory Diseases.
Armani E, Capaldi C, Bagnacani V, Saccani F, Aquino G, Puccini P, Facchinetti F, Martucci C, Moretto N, Villetti G, Patacchini R, Civelli M, Hurley C, Jennings A, Alcaraz L, Bloomfield D, Briggs M, Daly S, Panchal T, Russell V, Wicks S, Finch H, Fitzgerald M, Fox C, Delcanale M.
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 <b>1c</b> is outlined, where improvements in potency against p38α and ligand-enzyme dissociation kinetics led to several compounds showing pronounced anti-inflammatory effects <i>in vitro</i> (inhibition of TNFα release). Targeting of the defined physicochemical properties allowed the identification of compounds <b>3h</b>, <b>4e</b>, and <b>4f</b>, 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 <b>4e</b>, 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).