4,6-Diaminopyrimidines as Highly Preferred Troponin I‑Interacting Kinase (TNNI3K) Inhibitors

Structure-guided
progression of a purine-derived series of TNNI3K
inhibitors directed design efforts that produced a novel series of
4,6-diaminopyrimidine inhibitors, an emerging kinase binding motif.
Herein, we report a detailed understanding of the intrinsic conformational
preferences of the scaffold, which impart high specificity for TNNI3K.
Further manipulation of the template based on the conformational analysis
and additional structure–activity relationship studies provided
enhancements in kinase selectivity and pharmacokinetics that furnished
an advanced series of potent inhibitors. The optimized compounds (e.g.,
GSK854) are suitable leads for identifying new cardiac medicines and
have been employed as in vivo tools in investigational
studies aimed at defining the role of TNNI3K within heart failure.