Discovery and Toxicological Profiling of Aminopyridines as Orally Bioavailable Selective Inhibitors of PI3-Kinase γ
| Autor: | Colin Chinn, Clemence Tessier, Matthew Spendiff, Ajay Lal, Marguerite Bracher, Elisabeth Rosner, Gregory Hollingworth, Paul Nicklin, Andrew James Culshaw, Matthew Thomas, Stephen Marshall, Benjamin R. Bellenie, Edward Charles Hall, Ian N. Bruce, Kuno Wuersch, Ameet Vijay Ambarkhane, Julie Coote, Gillian Wallis, James Neef, Eva Cullen, Sarah McDonald |
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| Rok vydání: | 2021 |
| Předmět: |
Inflammation
No-Observed-Adverse-Effect Level Molecular Structure Kinase Chemistry Anti-Inflammatory Agents Airway inflammation Aminopyridines Pharmacology In vitro Bioavailability Rats Sprague-Dawley Structure-Activity Relationship Pharmacokinetics In vivo Pyrazines Drug Discovery Animals Class Ib Phosphatidylinositol 3-Kinase Humans Molecular Medicine Female Protein Kinase Inhibitors Whole blood |
| Zdroj: | Journal of Medicinal Chemistry. 64:12304-12321 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Using a novel physiologically relevant in vitro human whole blood neutrophil shape change assay, an aminopyrazine series of selective PI3Kγ inhibitors was identified and prioritized for further optimization. Severe solubility limitations associated with the series leading to low oral bioavailability and poor exposures, especially at higher doses, were overcome by moving to an aminopyridine core. Compound 33, with the optimal balance of on-target activity, selectivity, and pharmacokinetic parameters, progressed into in vivo studies and demonstrated good efficacy (10 mg/kg) in a rat model of airway inflammation. Sufficient exposures were achieved at high doses to support toxicological studies, where unexpected inflammatory cell infiltrates in cardiovascular tissue prevented further compound development. |
| Databáze: | OpenAIRE |
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