Substituent Effects on Drug–Receptor H‑bond Interactions: Correlations Useful for the Design of Kinase Inhibitors

Investigation of troponin I-interacting kinase (TNNI3K) as a potential target for the treatment of heart failure has produced a series of substituted <i>N</i>-methyl-3-(pyrimidin-4-ylamino)­benzenesulfonamide inhibitors that display excellent potency and selectivity against a broad spectrum of protein kinases. Crystal structures of prototypical members bound to the ATP-binding site of TNNI3K reveal two anchoring hydrogen bond contacts: (1) from the hinge region amide N–H to the pyrimidine nitrogen and (2) from the sulfonamide N–H to the gatekeeper threonine. Evaluation of various <i>para</i>-substituted benzenesulfonamides defined a substituent effect on binding affinity resulting from modulation of the sulfonamide H-bond donor strength. An opposite electronic effect emerged for the hinge NH-pyrimidine H-bond interaction, which is further illuminated in the correlation of calculated H-bond acceptor strength and TNNI3K affinity for a variety of hinge binding heterocycles. These fundamental correlations on drug–receptor H-bond interactions may be generally useful tools for the optimization of potency and selectivity in the design of kinase inhibitors

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 <i>in vivo</i> tools in investigational studies aimed at defining the role of TNNI3K within heart failure

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 <i>in vivo</i> tools in investigational studies aimed at defining the role of TNNI3K within heart failure

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 <i>in vivo</i> tools in investigational studies aimed at defining the role of TNNI3K within heart failure

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 <i>in vivo</i> tools in investigational studies aimed at defining the role of TNNI3K within heart failure

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 <i>in vivo</i> tools in investigational studies aimed at defining the role of TNNI3K within heart failure

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 <i>in vivo</i> tools in investigational studies aimed at defining the role of TNNI3K within heart failure

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 <i>in vivo</i> tools in investigational studies aimed at defining the role of TNNI3K within heart failure

Discovery of 3‑(5-Chloro-2-furoyl)-3,7-diazabicyclo[3.3.0]octane (TC-6683, AZD1446), a Novel Highly Selective α4β2 Nicotinic Acetylcholine Receptor Agonist for the Treatment of Cognitive Disorders

Diversification of essential nicotinic cholinergic pharmacophoric elements, i.e., cationic center and hydrogen bond acceptor, resulted in the discovery of novel potent α4β2 nAChR selective agonists comprising a series of <i>N</i>-acyldiazabicycles. Core characteristics of the series are an exocyclic carbonyl moiety as a hydrogen bond acceptor and endocyclic secondary amino group. These features are positioned at optimal distance and with optimal relative spatial orientation to provide near optimal interactions with the receptor. A novel potent and highly selective α4β2 nAChR agonist 3-(5-chloro-2-furoyl)-3,7-diazabicyclo[3.3.0]­octane (<b>56</b>, TC-6683, AZD1446) with favorable pharmaceutical properties and in vivo efficacy in animal models has been identified as a potential treatment for cognitive deficits associated with psychiatric or neurological conditions and is currently being progressed to phase 2 clinical trials as a treatment for Alzheimer’s disease

Identification of Purines and 7‑Deazapurines as Potent and Selective Type I Inhibitors of Troponin I‑Interacting Kinase (TNNI3K)

A series of cardiac troponin I-interacting kinase (TNNI3K) inhibitors arising from 3-((9<i>H</i>-purin-6-yl)­amino)-<i>N</i>-methyl-benzenesulfonamide (<b>1</b>) is disclosed along with fundamental structure–function relationships that delineate the role of each element of <b>1</b> for TNNI3K recognition. An X-ray structure of <b>1</b> bound to TNNI3K confirmed its Type I binding mode and is used to rationalize the structure–activity relationship and employed to design potent, selective, and orally bioavailable TNNI3K inhibitors. Identification of the 7-deazapurine heterocycle as a superior template (vs purine) and its elaboration by introduction of C4-benzenesulfonamide and C7- and C8–7-deazapurine substituents produced compounds with substantial improvements in potency (>1000-fold), general kinase selectivity (10-fold improvement), and pharmacokinetic properties (>10-fold increase in poDNAUC). Optimal members of the series have properties suitable for use in <i>in vitro</i> and <i>in vivo</i> experiments aimed at elucidating the role of TNNI3K in cardiac biology and serve as leads for developing novel heart failure medicines