Key result
Optimization of a purine-derived series produced 4,6-diaminopyrimidine TNNI3K inhibitors, such as GSK854, with enhanced kinase selectivity and pharmacokinetics for use in heart failure models.
May enable TNNI3K inhibitor testing in HF models; leaves open clinical efficacy.
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.
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Philp et al. (2018) studied Heart failure. 4,6-diaminopyrimidine TNNI3K inhibitors (e.g., GSK854) was evaluated on Kinase selectivity and pharmacokinetics. Optimization of a purine-derived series produced 4,6-diaminopyrimidine TNNI3K inhibitors, such as GSK854, with enhanced kinase selectivity and pharmacokinetics for use in heart failure models.
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