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Synfacts 2018; 14(10): 0999
DOI: 10.1055/s-0037-1610902
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of a Phosphoinositide 3-Kinase (PI3K) β Inhibitor

Contributor(s):
Philip Kocienski
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
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Further Information

Publication History

Publication Date:
17 September 2018 (online)

 
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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.


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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.


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