1. Piperidinyl-embeded chalcones possessing anti PI3Kδ inhibitory properties exhibit anti-atopic properties in preclinical models.
- Author
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Dumontet C, Beck G, Gardebien F, Haudecoeur R, Mathé D, Matera EL, Tourette A, Mattei E, Esmenjaud J, Boyère C, Nurisso A, Peuchmaur M, Pérès B, Bouchaud G, Magnan A, Monneret G, and Boumendjel A
- Subjects
- Animals, Asthma drug therapy, Asthma metabolism, Basophils physiology, Cell Degranulation drug effects, Chalcones therapeutic use, Dermatitis, Atopic metabolism, Disease Models, Animal, Drug Evaluation, Preclinical, Humans, Mice, Models, Molecular, Phosphatidylinositol 3-Kinases metabolism, Piperidines chemistry, Piperidines pharmacology, Piperidines therapeutic use, Protein Kinase Inhibitors therapeutic use, Basophils drug effects, Chalcones chemistry, Chalcones pharmacology, Dermatitis, Atopic drug therapy, Phosphoinositide-3 Kinase Inhibitors, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology
- Abstract
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 PI3Kδ isoform is much more selectively expressed, enabling therapeutic targeting of this isoform. Of particular interest PI3Kδ is expressed in human basophils and its inhibition has been shown to reduce anti-IgE induced basophil degranulation, suggesting that PI3Kδ 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-PI3Kδ properties that was investigated in preclinical models. Compound 18, namely 1-[2-hydroxy-4,6-dimethoxy-3-(N-methylpiperidin-4-yl)phenyl]-3-(2,4,6-trimethoxyphenyl)-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., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)
- Published
- 2018
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