生物利用度
化学
药理学
药代动力学
体内
离体
体外
炎症
生物化学
医学
内科学
生物
生物技术
作者
Benjamin R. Bellenie,Edward Hall,Ian Bruce,Matthew Spendiff,Andrew J. Culshaw,Sarah D. McDonald,Ameet Ambarkhane,Colin Chinn,Matthew Thomas,Elisabeth Rosner,Marguerite Bracher,Paul Nicklin,Stephen Marshall,Julie Coote,Eva Cullen,Clemence Tessier,Kuno Wuersch,Ajay Lal,Gillian A. Wallis,Gregory J. Hollingworth,James Neef
标识
DOI:10.1021/acs.jmedchem.1c00986
摘要
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.
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