Details

Autor(en) / Beteiligte

• Jackson, Jeffrey J.
• Siegmund, Aaron C.
• Bai, Wen-Ju
• Reed, Anthony B.
• Birkholz, Adam B.
• Campuzano, Iain D. G.
• Créquer-Grandhomme, Amandine
• Hu, Ruozhen
• Modak, Rucha V.
• Sudom, Athena
• Javier, Noelle
• Sanders, Christiana
• Lo, Mei-Chu
• Xie, Fang
• Cee, Victor J.
• Manzanillo, Paolo
• Allen, John G.

Titel

Imidazolone as an Amide Bioisostere in the Development of β‑1,3‑N‑Acetylglucosaminyltransferase 2 (B3GNT2) Inhibitors

Ist Teil von

• Journal of medicinal chemistry, 2023-12, Vol.66 (23), p.16120-16140

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.