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

Autor:	Armani E; Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy., Capaldi C; Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy., Bagnacani V; Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy., Saccani F; Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy., Aquino G; Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy., Puccini P; Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy., Facchinetti F; Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy., Martucci C; Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy., Moretto N; Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy., Villetti G; Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy., Patacchini R; Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy., Civelli M; Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy., Hurley C; Charles River Laboratories, 8/9 Spire Green Centre, Flex Meadow, Harlow CM19 5TR, United Kingdom., Jennings A; Charles River Laboratories, 8/9 Spire Green Centre, Flex Meadow, Harlow CM19 5TR, United Kingdom., Alcaraz L; Charles River Laboratories, 8/9 Spire Green Centre, Flex Meadow, Harlow CM19 5TR, United Kingdom., Bloomfield D; Charles River Laboratories, 8/9 Spire Green Centre, Flex Meadow, Harlow CM19 5TR, United Kingdom., Briggs M; Charles River Laboratories, 8/9 Spire Green Centre, Flex Meadow, Harlow CM19 5TR, United Kingdom., Daly S; Charles River Laboratories, 8/9 Spire Green Centre, Flex Meadow, Harlow CM19 5TR, United Kingdom., Panchal T; Charles River Laboratories, 8/9 Spire Green Centre, Flex Meadow, Harlow CM19 5TR, United Kingdom., Russell V; Charles River Laboratories, 8/9 Spire Green Centre, Flex Meadow, Harlow CM19 5TR, United Kingdom., Wicks S; Charles River Laboratories, 8/9 Spire Green Centre, Flex Meadow, Harlow CM19 5TR, United Kingdom., Finch H; Pulmagen Therapeutics, The Coach House, Grenville Court Britwell Road, Burnham, Slough SL1 8DF, United Kingdom., Fitzgerald M; Pulmagen Therapeutics, The Coach House, Grenville Court Britwell Road, Burnham, Slough SL1 8DF, United Kingdom., Fox C; Pulmagen Therapeutics, The Coach House, Grenville Court Britwell Road, Burnham, Slough SL1 8DF, United Kingdom., Delcanale M; Chiesi Farmaceutici S.p.A, Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2022 May 26; Vol. 65 (10), pp. 7170-7192. Date of Electronic Publication: 2022 May 11.
DOI:	10.1021/acs.jmedchem.2c00115
Abstrakt:	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).
Databáze:	MEDLINE
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