title: Identification of Purines and 7-Deazapurines as Potent and Selective Type I Inhibitors of Troponin I-Interacting Kinase (TNNI3K).
abstract: 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 of each element of 1 for TNNI3K recognition. An X-ray structure of 1 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 in vitro and in vivo experiments aimed at elucidating the role of TNNI3K in cardiac biology and serve as leads for developing novel heart failure medicines.
authors.affiliation: Heart Failure Discovery Performance Unit and ‡Platform Technology and Sciences, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Lawhorn
authors.affiliation: Heart Failure Discovery Performance Unit and ‡Platform Technology and Sciences, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Joanne
authors.initials: J
authors.lastname: Philp
authors.affiliation: Heart Failure Discovery Performance Unit and ‡Platform Technology and Sciences, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Yongdong
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Heart Failure Discovery Performance Unit and ‡Platform Technology and Sciences, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Louer
authors.affiliation: Heart Failure Discovery Performance Unit and ‡Platform Technology and Sciences, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Marlys
authors.initials: M
authors.lastname: Hammond
authors.affiliation: Heart Failure Discovery Performance Unit and ‡Platform Technology and Sciences, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Mui
authors.initials: M
authors.lastname: Cheung
authors.affiliation: Heart Failure Discovery Performance Unit and ‡Platform Technology and Sciences, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Harvey
authors.initials: H
authors.lastname: Fries
authors.affiliation: Heart Failure Discovery Performance Unit and ‡Platform Technology and Sciences, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Graves
authors.affiliation: Heart Failure Discovery Performance Unit and ‡Platform Technology and Sciences, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Lisa
authors.initials: L
authors.lastname: Shewchuk
authors.affiliation: Heart Failure Discovery Performance Unit and ‡Platform Technology and Sciences, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.affiliation: Heart Failure Discovery Performance Unit and ‡Platform Technology and Sciences, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Cottom
authors.affiliation: Heart Failure Discovery Performance Unit and ‡Platform Technology and Sciences, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Qi
authors.affiliation: Heart Failure Discovery Performance Unit and ‡Platform Technology and Sciences, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Huizhen
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Heart Failure Discovery Performance Unit and ‡Platform Technology and Sciences, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Rachel
authors.initials: R
authors.lastname: Totoritis
authors.affiliation: Heart Failure Discovery Performance Unit and ‡Platform Technology and Sciences, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Guofeng
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Heart Failure Discovery Performance Unit and ‡Platform Technology and Sciences, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schwartz
authors.affiliation: Heart Failure Discovery Performance Unit and ‡Platform Technology and Sciences, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Hu
authors.initials: H
authors.lastname: Li
authors.affiliation: Heart Failure Discovery Performance Unit and ‡Platform Technology and Sciences, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Sharon
authors.initials: S
authors.lastname: Sweitzer
authors.affiliation: Heart Failure Discovery Performance Unit and ‡Platform Technology and Sciences, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Holt
authors.affiliation: Heart Failure Discovery Performance Unit and ‡Platform Technology and Sciences, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gatto
authors.affiliation: Heart Failure Discovery Performance Unit and ‡Platform Technology and Sciences, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
authors.forename: Lara S
authors.initials: LS
authors.lastname: Kallander
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D008297:Male; D011485:Protein Binding; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases; D011687:Purines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D011687:Purines; D013449:Sulfonamides; D017346:Protein Serine-Threonine Kinases; C481078:TNNI3K protein, human; D020930:MAP Kinase Kinase Kinases