posted on 2023-11-21, 21:20authored byJeffrey J. Jackson, Aaron C. Siegmund, Wen-Ju Bai, Anthony B. Reed, Adam B. Birkholz, Iain D. G. Campuzano, Amandine Créquer-Grandhomme, Ruozhen Hu, Rucha V. Modak, Athena Sudom, Noelle Javier, Christiana Sanders, Mei-Chu Lo, Fang Xie, Victor J. Cee, Paolo Manzanillo, John G. Allen
B3GNT2 is responsible for elongation
of cell surface long-chain
polylactosamine, which influences the regulation of the immune response,
making it an attractive target for immunomodulation. In the development
of amide containing B3GNT2 inhibitors guided by structure-based drug
design, imidazolones were found to successfully serve as amide bioisosteres.
This novel imidazolone isosteric strategy alleviated torsional strain
of the amide bond on binding to B3GNT2 and improved potency, isoform
selectivity, as well as certain physicochemical and pharmacokinetic
properties. Herein, we present the synthesis, SAR, X-ray cocrystal
structures, and in vivo PK properties of imidazol-4-ones
in the context of B3GNT2 inhibition.