Bellenie, Benjamin R.; Hall, Edward; Bruce, Ian; Spendiff, Matthew; Culshaw, Andrew; McDonald, Sarah; Ambarkhane, Ameet; Chinn, Colin; Thomas, Matthew; Rosner, Elisabeth; Bracher, Marguerite; Nicklin, Paul; Marshall, Stephen; Coote, Julie; Cullen, Eva; Tessier, Clemence; Wuersch, Kuno; Lal, Ajay; Wallis, Gillian; Hollingworth, Gregory J.; Neef, James published the artcile< Discovery and Toxicological Profiling of Aminopyridines as Orally Bioavailable Selective Inhibitors of PI3-Kinase γ>, Quality Control of 1046832-21-6, the main research area is pharmacokinetic aminopyridine oral inhibitor PI3K gamma airway inflammation toxicol.
Using a novel physiol. 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 toxicol. studies, where unexpected inflammatory cell infiltrates in cardiovascular tissue prevented further compound development.
Journal of Medicinal Chemistry published new progress about Aminopyridines Role: PAC (Pharmacological Activity), SPN (Synthetic Preparation), THU (Therapeutic Use), BIOL (Biological Study), PREP (Preparation), USES (Uses). 1046832-21-6 belongs to class pyrazoles-derivatives, and the molecular formula is C11H19BN2O2, Quality Control of 1046832-21-6.
Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics