molecules of the month

“compound 38a”

orally active ChemR23 GPCR inhibitor

oral effects on dendritic cells in higher species

from cell-based screen and optimization

Bioorg. Med. Chem., Jul. 14, 2020

Kyowa Kirin, Shizuoka, JP

Structure of compound 38a
1 min read

“compound 38a” is an inhibitor of ChemR23, a chemokine-receptor-like GPCR with a role in plasmacytoid dendritic cell (pDC) trafficking. The ChemR23 inhibitor was developed with the intention of suppressing the migration of pDCs, which may be useful in certain autoimmune diseases. A key change that dramatically improved bioavailability was swapping a tetrazole with the 1,2,4-oxadiazol-5-one ring. The 1,2,4-oxadiazol-5-one is often proposed as a carboxylic acid isostere but I was surprised to see such a dramatic effect on bioavailability. It’s also surprising that the final compound, which bears two negatively charged groups (acid + oxadizolone) has significant oral exposure in monkeys.

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