Back to Search
Start Over
Piperidinyl-embeded chalcones possessing anti PI3Kδ inhibitory properties exhibit anti-atopic properties in preclinical models
- Source :
- European Journal of Medicinal Chemistry, European Journal of Medicinal Chemistry, Elsevier, 2018, 158, pp.405-413. ⟨10.1016/j.ejmech.2018.09.033⟩
- Publication Year :
- 2018
-
Abstract
- International audience; Phosphatidylinositide 3-kinases (PI3Ks) are widely expressed enzymes involved in membrane signalization pathways. Attempts to administer inhibitors with broad activity against different isoforms have failed due to toxicity. Conversely the PI3K delta isoform is much more selectively expressed, enabling therapeutic targeting of this isoform. Of particular interest PI3K delta is expressed in human basophils and its inhibition has been shown to reduce anti-IgE induced basophil degranulation, suggesting that PI3K delta inhibitors could be useful as anti-allergy drugs. Herein, we report for the first time the activity of compounds derived from chalcone scaffolds as inhibitors of normal human basophil degranulation and identified the most active compound with anti-PI3K delta properties that was investigated in preclinical models. Compound 18, namely 1-[2-hydroxy-4,6-dimethoxy-3-(N-methylpiperidin-4-yl)pheny1]-3(2,4,6-trimethoxypheny1)-prop-2-en-1-one, was found to inhibit normal human basophil degranulation in a dose-dependent manner. In a murine model of ovalbumin-induced asthma, compound 18 was shown to reduce expiratory pressure while its impact on the inflammatory infiltrate in alveolar lavage and total lung was dependent on the route of administration. In a DNFB-induced model of atopic dermatitis compound 18 administered systemically proved to be as potent as topical betamethasone. These results support the anti-atopic and allergic properties of the title compound and warrant further clinical development. (C) 2018 Elsevier Masson SAS
- Subjects :
- 0301 basic medicine
Gene isoform
Models, Molecular
Chalcone
Drug Evaluation, Preclinical
Pharmacology
Basophil degranulation
Cell Degranulation
Dermatitis, Atopic
03 medical and health sciences
chemistry.chemical_compound
Route of administration
Mice
Phosphatidylinositol 3-Kinases
Chalcones
Piperidines
Drug Discovery
[SDV.IDA]Life Sciences [q-bio]/Food engineering
medicine
Animals
Humans
[SPI.GPROC]Engineering Sciences [physics]/Chemical and Process Engineering
Allergic properties
Protein Kinase Inhibitors
PI3K delta
Phosphoinositide-3 Kinase Inhibitors
chemistry.chemical_classification
Chemistry
Organic Chemistry
Degranulation
General Medicine
Atopic dermatitis
medicine.disease
Asthma
3. Good health
Basophils
Disease Models, Animal
030104 developmental biology
Enzyme
Anti-atopic activity
Toxicity
Subjects
Details
- ISSN :
- 17683254 and 02235234
- Volume :
- 158
- Database :
- OpenAIRE
- Journal :
- European journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....9ca7e0dfbd92df260affaada5241699e