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

作者：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; Villasenor Armando G; Zherebina Yelena; Perreault Stephane^*

来源：Journal of Medicinal Chemistry, 2018, 61(15): 6858-6868.

DOI：10.1021/acs.jmedchem.8b00797

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) beta 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 PI3K beta inhibitor.

• 出版日期2018-8-9