Stable C-N axial chirality in 1-aryluracil scaffold and differences in in vitro metabolic clearance between atropisomers of PDE4 inhibitor.

ID: ALA4043107

Journal: Bioorg Med Chem

Title: Stable C-N axial chirality in 1-aryluracil scaffold and differences in in vitro metabolic clearance between atropisomers of PDE4 inhibitor.

Authors: Hasegawa F, Kawamura K, Tsuchikawa H, Murata M.

Abstract: We report herein the stable C-N axial chirality in a 1-phenyl-6-aminouracil scaffold owing to the presence of various functional groups at the ortho-position of the N(1)-phenyl group. Racemic 1-phenyl-6-aminouracils were first separated by chiral HPLC or converting them to the corresponding diastereomers using a chiral resolving agent. We then determined the rotational barrier of each atropisomer by a thermal racemization method and found that these compounds have rotational barriers similar to other C-N axially chiral biaryls. In addition, there was a good correlation between the rotational barriers and van der Waals radii of an ortho-substituent of the N(1)-phenyl group. To explore the possibility of the chiral 1-phenyl-6-aminouracil scaffold as a drug lead, we synthesized both atropisomers as phosphodiesterase-4 inhibitors 10. The atropisomers showed significantly different metabolic stabilities while their PDE4 inhibitory activities were somewhat similar. This finding demonstrates the potential utility of stable C-N bond atropisomers in the development of chiral drugs.

CiteXplore: 28698053

DOI: 10.1016/j.bmc.2017.06.042

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