The synthesis and structure–activity relationship studies of selective acetyl-CoA carboxylase inhibitors containing 4-(thiazol-5-yl)but-3-yn-2-amino motif: Polar region modifications

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Abstract

The structure–activity relationship study focused on the polar region of the HTS hit A-80040 (1) producing several series of potent and selective ACC2 inhibitors. The SAR suggests a compact lipophilic pocket that does not tolerate polar and ionic groups. Replacement of the hydroxyurea group with isoxazoles improves ACC2 selectivity while maintaining potency. Variations at the propargylic site of 11a reduce ACC2 potency.

Graphical abstract

Potent and selective ACC2 inhibitors were synthesized by modifying the polar region of a HTS hit and the SAR suggests a compact and lipophilic binding pocket.

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Acknowledgments

We thank Richard F. Clark and Dr. Teresa McNally for their helpful suggestions in the preparation of this manuscript.

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Present address: Exploratory Clinical Development, Novartis Pharmaceuticals, East Hanover, NJ 07936, USA.

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