2. Academic Validation
  3. Application of an "inhalation by design" approach to the identification and in-vitro evaluation of novel purine based PI3Kδ inhibitors

Application of an "inhalation by design" approach to the identification and in-vitro evaluation of novel purine based PI3Kδ inhibitors

  • Eur J Med Chem. 2023 Jun 5;254:115331. doi: 10.1016/j.ejmech.2023.115331.
Roberta Mazzucato 1,  Marinella Roberti 2,  Anna Maria Capelli 3,  Fabio Rancati 4,  Matteo Biagetti 5,  Claudio Fiorelli 4,  Paolo Bruno 4,  Paolo Ronchi 4,  Serena Bertolini 6,  Mauro Corsi 7,  Daniele Pala 8
Affiliations

Affiliations

  • 1 Chemistry Research and Drug Design Department, Chiesi Farmaceutici S.p.A, Nuovo Centro Ricerche, Largo Belloli 11/a, 43122, Parma, Italy. Electronic address: [email protected].
  • 2 Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy.
  • 3 Corporate Drug Development, Chiesi Farmaceutici S.p.A, Nuovo Centro Ricerche, Largo Belloli 11/a, 43122, Parma, Italy.
  • 4 Chemistry Research and Drug Design Department, Chiesi Farmaceutici S.p.A, Nuovo Centro Ricerche, Largo Belloli 11/a, 43122, Parma, Italy.
  • 5 Pipeline Innovation Department, Chiesi Farmaceutici S.p.A, Nuovo Centro Ricerche, Largo Belloli 11/a, 43122, Parma, Italy.
  • 6 Experimental Pharmacology and Translational Science, Chiesi Farmaceutici S.p.A, Nuovo Centro Ricerche, Largo Belloli 11/a, 43122, Parma, Italy.
  • 7 In Vitro Biology Department, Aptuit, an Evotec Company, Via A. Fleming 4, 37135, Verona, Italy.
  • 8 Chemistry Research and Drug Design Department, Chiesi Farmaceutici S.p.A, Nuovo Centro Ricerche, Largo Belloli 11/a, 43122, Parma, Italy. Electronic address: [email protected].
PMID: 37094451 DOI: 10.1016/j.ejmech.2023.115331
Abstract

PI3Kδ is a lipid kinase which plays a key role in airway inflammatory conditions. Accordingly, the inhibition of PI3Kδ can be considered a valuable strategy for the treatment of chronic respiratory diseases such as Asthma and Chronic obstructive pulmonary disease (COPD). In this work, we describe our efforts to identify new PI3Kδ inhibitors following an "inhalation by design" strategy. Starting from the identification of a purine scaffold, we carried out a preliminary SAR expansion which led to the identification of a new hit characterized by a high enzymatic potency and moderate PI3Kδ selectivity. A subsequent optimization led to novel purine based derivatives with favorable in vitro ADME profiles, which might represent promising starting points for future development of new inhaled drug candidates.

Keywords

Asthma; Chronic obstructive pulmonary disease (COPD); Chronic respiratory diseases; Inhalation by design; PI3-kinases (PI3Ks); PI3Kδ.

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