2. Academic Validation
  3. Discovery and Optimization of Pyridazinones as PI3Kδ Selective Inhibitors for Administration by Inhalation

Discovery and Optimization of Pyridazinones as PI3Kδ Selective Inhibitors for Administration by Inhalation

  • J Med Chem. 2024 Jul 11;67(13):11103-11124. doi: 10.1021/acs.jmedchem.4c00610.
Paolo Bruno 1,  Alessandra Micoli 2,  Mauro Corsi 3,  Daniele Pala 1,  Sara Guariento 1,  Claudio Fiorelli 1,  Paolo Ronchi 1,  Alessandro Fioni 4,  Paola Maria Gallo 4,  Giulia Marenghi 4,  Serena Bertolini 5,  Silvia Capacchi 1,  Valentina Mileo 6,  Matteo Biagetti 7,  Anna Maria Capelli 8
Affiliations

Affiliations

  • 1 Medicinal Chemistry and Drug Design Technologies Department, Chiesi Farmaceutici S.p.A, Nuovo Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy.
  • 2 Drug Discovery Chemistry Department, Aptuit, an Evotec Company, Via A. Fleming 4, 37135 Verona, Italy.
  • 3 In Vitro Biology Department, Aptuit, an Evotec Company, Via A. Fleming 4, 37135 Verona, Italy.
  • 4 Pharmacokinetics Biochemistry Metabolism Department, Chiesi Farmaceutici S.p.A, Nuovo Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy.
  • 5 Pharmacology Department, Chiesi Farmaceutici S.p.A, Nuovo Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy.
  • 6 Analytics & Early Formulations Department, Chiesi Farmaceutici S.p.A, Nuovo Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy.
  • 7 Pipeline Innovation Department, Chiesi Farmaceutici S.p.A, Nuovo Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy.
  • 8 AIR Franchise, Chiesi Farmaceutici S.p.A, Nuovo Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy.
PMID: 38907711 DOI: 10.1021/acs.jmedchem.4c00610
Abstract

A hit-to-lead campaign pursuing the identification of novel inhalant small-molecule phosphatidylinositol 3-kinase (PI3K) inhibitors for the treatment of inflammatory respiratory diseases is disclosed. A synthetically versatile pyridazin-3(2H)-one scaffold was designed, and three exit vectors on the core moiety were used to explore chemical diversity and optimize pharmacological and absorption, distribution, metabolism, and excretion (ADME) properties. Desired modulation of PI3Kδ selectivity and cellular potency as well as ADME properties in view of administration by inhalation was achieved. Intratracheal administration of lead compound 26 resulted in a promising pharmacokinetic profile, thus demonstrating that the optimization strategy of in vitro profiles successfully translated to an in vivo setting.

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