1301760-69-9Relevant academic research and scientific papers
Substituent Effects on Drug-Receptor H-bond Interactions: Correlations Useful for the Design of Kinase Inhibitors
Lawhorn, Brian G.,Philp, Joanne,Graves, Alan P.,Holt, Dennis A.,Gatto, Gregory J.,Kallander, Lara S.
, p. 10629 - 10641 (2016/12/16)
Investigation of troponin I-interacting kinase (TNNI3K) as a potential target for the treatment of heart failure has produced a series of substituted N-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 para-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.
QUINAZOLINE COMPOUNDS
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Page/Page column 52, (2011/06/11)
Disclosed are compounds having the formula: wherein R1, R2, R3, R4, R5, R6 and R7 are as defined herein, and methods of making and using the same.
