Atropisomerism by Design: Discovery of a Selective and Stable Phosphoinositide 3‑Kinase (PI3K) β Inhibitor

Atropisomerism is a type of axial chirality in which enantiomers or diastereoisomers arise due to hindered rotation around a bond axis. In this manuscript, we report a case in which torsional scan studies guided the thoughtful creation of a restricted axis of rotation between two heteroaromatic syst...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2018-08, Vol.61 (15), p.6858-6868
Main Authors: Chandrasekhar, Jayaraman, Dick, Ryan, Van Veldhuizen, Joshua, Koditek, David, Lepist, Eve-Irene, McGrath, Mary E, Patel, Leena, Phillips, Gary, Sedillo, Kassandra, Somoza, John R, Therrien, Joseph, Till, Nicholas A, Treiberg, Jennifer, Villaseñor, Armando G, Zherebina, Yelena, Perreault, Stephane
Format: Article
Language:English
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Summary:Atropisomerism is a type of axial chirality in which enantiomers or diastereoisomers arise due to hindered rotation around a bond axis. In this manuscript, we report a case in which torsional scan studies guided the thoughtful creation of a restricted axis of rotation between two heteroaromatic systems of a phosphoinositide 3-kinase (PI3K) β inhibitor, generating a pair of atropisomeric compounds with significantly different pharmacological and pharmacokinetic profiles. Emblematic of these differences, the metabolism of inactive (M)-28 is primarily due to the cytosolic enzyme aldehyde oxidase, while active (P)-28 has lower affinity for aldehyde oxidase, resulting in substantially better metabolic stability. Additionally, we report torsional scan and experimental studies used to determine the barriers of rotation of this novel PI3Kβ inhibitor.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.8b00797