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Discovery and Optimization of Pyridazinones as PI3Kδ Selective Inhibitors for Administration by Inhalation
Paolo Bruno1, Alessandra Micoli2, Mauro Corsi3
1Medicinal Chemistry and Drug Design Technologies Department, Chiesi Farmaceutici S.p.A, Nuovo Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy.
Journal of Medicinal Chemistry
|June 22, 2024
Summary
Researchers developed novel inhaled small-molecule inhibitors targeting phosphatidylinositol 3-kinase (PI3K) for inflammatory respiratory diseases. Lead compound 26 showed promising in vivo pharmacokinetics after intratracheal administration, validating the in vitro to in vivo translation.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Respiratory Medicine
Background:
- Inflammatory respiratory diseases represent a significant unmet medical need.
- Phosphatidylinositol 3-kinase (PI3K) signaling pathways are implicated in inflammation.
- Development of inhaled therapies offers targeted delivery for respiratory conditions.
Purpose of the Study:
- To identify novel small-molecule inhibitors of PI3K for treating inflammatory respiratory diseases.
- To optimize compounds for inhalation delivery, focusing on pharmacological and ADME properties.
- To evaluate the in vivo efficacy and pharmacokinetic profile of lead compounds.
Main Methods:
- Design and synthesis of a pyridazin-3(2H)-one scaffold with three diversification points.
- Exploration of chemical diversity to optimize PI3Kδ selectivity, cellular potency, and ADME properties.
- Intratracheal administration of lead compound 26 in an in vivo model.
Main Results:
- Achieved desired modulation of PI3Kδ selectivity and cellular potency.
- Optimized absorption, distribution, metabolism, and excretion (ADME) properties suitable for inhalation.
- Lead compound 26 demonstrated a promising pharmacokinetic profile upon intratracheal administration.
Conclusions:
- The developed pyridazin-3(2H)-one scaffold is a versatile platform for discovering inhaled PI3K inhibitors.
- The optimization strategy successfully translated in vitro profiles to in vivo performance.
- This approach holds potential for developing new inhaled therapeutics for inflammatory respiratory diseases.
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