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...

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Published inJournal of medicinal chemistry Vol. 65; no. 10; pp. 7170 - 7192
Main Authors Armani, Elisabetta, Capaldi, Carmelida, Bagnacani, Valentina, Saccani, Francesca, Aquino, Giancarlo, Puccini, Paola, Facchinetti, Fabrizio, Martucci, Cataldo, Moretto, Nadia, Villetti, Gino, Patacchini, Riccardo, Civelli, Maurizio, Hurley, Chris, Jennings, Andrew, Alcaraz, Lilian, Bloomfield, Dawn, Briggs, Michael, Daly, Stephen, Panchal, Terry, Russell, Vince, Wicks, Sharon, Finch, Harry, Fitzgerald, Mary, Fox, Craig, Delcanale, Maurizio
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 26.05.2022
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
ACTIVATED PROTEIN-KINASE
KINETICS
AIRWAY INFLAMMATION
PREVENTION
BINDING
COPD
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Summary: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).
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.2c00115