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

Journal of Medicinal Chemistry
Jayaraman ChandrasekharStephane Perreault

Abstract

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.

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Citations

Jan 3, 2019·Endocrinology·Anne R Bresnick, Jonathan M Backer
Mar 1, 2019·Biomolecules·Michelle S MillerSandra B Gabelli
Nov 12, 2019·Chemistry : a European Journal·Andrew BallardAndrew G Leach
Mar 12, 2020·Angewandte Chemie·Joanna Wencel-DelordFrançoise Colobert
Jan 22, 2021·Future Medicinal Chemistry·Sean T ToenjesJeffrey L Gustafson
May 13, 2021·Organic Letters·Jiamiao JinYonggui Robin Chi
Jun 16, 2021·Nature Reviews. Drug Discovery·Bart VanhaesebroeckKlaus Okkenhaug
Aug 7, 2019·Journal of Medicinal Chemistry·Nenad ManevskiFrancesca Toselli
Jun 20, 2020·ACS Medicinal Chemistry Letters·Stephane PerreaultGary Phillips

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