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Discovery of CHF-6523, an Inhaled Selective PI3Kδ Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease.

Discovery of CHF-6523, an Inhaled Selective PI3Kδ Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease.

Authors :
Bruno P
Pala D
Micoli A
Corsi M
Accetta A
Carzaniga L
Ronchi P
Fiorelli C
Formica M
Pizzirani D
Mazzucato R
Guariento S
Bertolini S
Martucci C
Allen AD
Mileo V
Capacchi S
Gallo PM
Fioni A
Xanxo Fernandez S
Villetti G
Puccini P
Civelli M
Guala M
Retini M
Martinelli P
Visentini F
Pavoni V
Daldosso M
Fontana S
Biagetti M
Capelli AM
Source :
Journal of medicinal chemistry [J Med Chem] 2024 Dec 05. Date of Electronic Publication: 2024 Dec 05.
Publication Year :
2024
Publisher :
Ahead of Print

Abstract

The design of inhaled selective phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitors for the treatment of inflammatory lung diseases was pursued. Knowledge-based design of a novel isocoumarin scaffold that was able to adopt a propeller-shape topology ensured the desired PI3Kδ selectivity. Achievement of low nanomolar cellular potencies through hinge binder group optimization, reduction of intrinsic permeability through head group optimization to extend lung retention, and screening of crystalline forms suitable for administration as dry powders culminated in the identification of compound 18 . This novel inhaled selective PI3Kδ inhibitor displayed durable anti-inflammatory activity in a disease-relevant rat model of Th-2-driven acute lung inflammation and safe in vitro and in vivo preclinical profiles. Therefore, compound 18 showed the appropriate discovery profile and was progressed to clinical trials in healthy volunteers and chronic obstructive pulmonary disease (COPD) patients as CHF-6523.

Details

Language :
English
ISSN :
1520-4804
Database :
MEDLINE
Journal :
Journal of medicinal chemistry
Publication Type :
Academic Journal
Accession number :
39635891
Full Text :
https://doi.org/10.1021/acs.jmedchem.4c02062