Identification of Purines and 7-Deazapurines as Potent and Selective Type I Inhibitors of Troponin I-Interacting Kinase (TNNI3K).
作者： Brian G. Lawhorn , Joanne Philp , Yongdong Zhao , Christopher Louer , Marlys Hammond
DOI: 10.1021/ACS.JMEDCHEM.5B00931
关键词: Troponin I 、 MAP kinase kinase kinase 、 Kinase 、 Biochemistry 、 Chemistry 、 Purine metabolism 、 Structure–activity relationship 、 Plasma protein binding 、 Stereochemistry 、 Purine 、 In vivo
摘要: A series of cardiac troponin I-interacting kinase (TNNI3K) inhibitors arising from 3-((9H-purin-6-yl)amino)-N-methyl-benzenesulfonamide (1) is disclosed along with fundamental structure–function relationships that delineate the role each element 1 for TNNI3K recognition. An X-ray structure bound to confirmed its Type I binding mode and used rationalize structure–activity relationship employed design potent, selective, orally bioavailable inhibitors. Identification 7-deazapurine heterocycle as a superior template (vs purine) elaboration by introduction C4-benzenesulfonamide C7- C8–7-deazapurine substituents produced compounds substantial improvements in potency (>1000-fold), general selectivity (10-fold improvement), pharmacokinetic properties (>10-fold increase poDNAUC). Optimal members have suitable use vitro vivo experiments aimed at elucidating cardi...
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