Discovery of a Series of Pyrimidine Carboxamides as Inhibitors of Vanin‑1

A diaryl
ketone series was identified as vanin-1 inhibitors from
a high-throughput screening campaign. While this novel scaffold provided
valuable probe 2 that was used to build target confidence,
concerns over the ketone moiety led to the replacement of this group.
The successful replacement of this moiety was achieved with pyrimidine
carboxamides derived from cyclic secondary amines that were extensively
characterized using biophysical and crystallographic methods as competitive
inhibitors of vanin-1. Through optimization of potency and physicochemical
and ADME properties, and guided by co-crystal structures with vanin-1, 3 was identified with a suitable profile for advancement into
preclinical development.