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Design, Synthesis, and Biological Characterization of Inhaled p38α/ß MAPK Inhibitors for the Treatment of Lung Inflammatory Diseases.
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.
Afiliación
  • 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.
J Med Chem ; 65(10): 7170-7192, 2022 05 26.
Article en En | MEDLINE | ID: mdl-35546685
The identification of novel inhaled p38α/ß 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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neumonía / Proteínas Quinasas p38 Activadas por Mitógenos / Proteína Quinasa 14 Activada por Mitógenos / Inhibidores de Proteínas Quinasas Límite: Animals Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2022 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neumonía / Proteínas Quinasas p38 Activadas por Mitógenos / Proteína Quinasa 14 Activada por Mitógenos / Inhibidores de Proteínas Quinasas Límite: Animals Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2022 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Estados Unidos