Perreault S.
* Gilead Sciences, Inc., Seattle and Foster City, USA
Atropisomerism by Design: Discovery of a Selective and Stable Phosphoinositide 3-Kinase (PI3K) β Inhibitor.
J. Med. Chem. 2018;
61: 6858-6868
Key words
phosphoinositide 3-kinase β inhibitor - aldehyde oxidase - atropisomers - benzimidazole ring formation - 1,2,4-triazole ring formation - Suzuki–Miyaura coupling
Significance
The target molecule K is a phosphoinositide 3-kinase (PI3K) β Inhibitor that is of interest for the treatment of various cancers. The restricted axis of rotation around a carbon–nitrogen bond of rac-K generated atropisomeric compounds (P)-K and (M)-K with significantly different pharmacological and pharmacokinetic profiles.
Comment
The metabolism of the inactive atropisomer (M)-K is the result of the action of the enzyme aldehyde oxidase (AO) whereas the active atropisomer (P)-K has lower affinity for AO resulting in better metabolic stability. The atropisomers (∆Erot = 35 kcal/mol) were separated by preparative chiral SFC chromatography.
