Sulfoximine-substituted trifluoromethylpyrimidine analogs as inhibitors of proline-rich tyrosine kinase 2 (PYK2) show reduced hERG activity

The synthesis, in vitro properties, and in vivo pharmacokinetics for a series of sulfoximine-substituted trifluoromethylpyrimidines as inhibitors of proline-rich tyrosine kinase, a target for the possible treatment of osteoporosis, are described. These compounds were prepared as surrogates of the corresponding sulfone compound 1. Sulfone 1 was an attractive PYK2 lead compound; however, subsequent studies determined this compound possessed high dofetilide binding, which is an early indicator of cardiovascular safety. Surprisingly, the corresponding sulfoximine analogs displayed significantly lower dofetilide binding, which, for N-methylsulfoximine (S)-14a, translated to lower activity in a patch clamp hERG K+ ion channel screen. In addition, compound (S)-14a shows good oral exposure in a rat pharmacokinetic model.

Graphical abstractSynthesis and in vitro activity for a series sulfoximine-substituted trifluoromethylpyrimine analogs as inhibitors of PYK2 are described. Compared to the corresponding sulfone analog, the sulfoximines surprisingly showed significantly lower dofetilide binding activity, which is an early indicator of cardiovascular safety.Figure optionsDownload full-size imageDownload as PowerPoint slide