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

  • J Med Chem. 2022 May 26;65(10):7170-7192. doi: 10.1021/acs.jmedchem.2c00115.
Elisabetta Armani  1 ,  Carmelida Capaldi  1 ,  Valentina Bagnacani  1 ,  Francesca Saccani  1 ,  Giancarlo Aquino  1 ,  Paola Puccini  1 ,  Fabrizio Facchinetti  1 ,  Cataldo Martucci  1 ,  Nadia Moretto  1 ,  Gino Villetti  1 ,  Riccardo Patacchini  1 ,  Maurizio Civelli  1 ,  Chris Hurley  2 ,  Andrew Jennings  2 ,  Lilian Alcaraz  2 ,  Dawn Bloomfield  2 ,  Michael Briggs  2 ,  Stephen Daly  2 ,  Terry Panchal  2 ,  Vince Russell  2 ,  Sharon Wicks  2 ,  Harry Finch  3 ,  Mary Fitzgerald  3 ,  Craig Fox  3 ,  Maurizio Delcanale  1
Affiliations
  • 1. Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy.
  • 2. Charles River Laboratories, 8/9 Spire Green Centre, Flex Meadow, Harlow CM19 5TR, United Kingdom.
  • 3. Pulmagen Therapeutics, The Coach House, Grenville Court Britwell Road, Burnham, Slough SL1 8DF, United Kingdom.
PMID: 35546685 DOI: 10.1021/acs.jmedchem.2c00115
Abstract

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).

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