Identification of Purines and 7-Deazapurines as Potent and Selective Type I Inhibitors of Troponin I-Interacting Kinase (TNNI3K)
| Autor: | Dennis A. Holt, Gatto Gregory J, Joanne Philp, Sharon Sweitzer, Marlys Hammond, Guofeng Zhang, Mui Cheung, Rachel D. Totoritis, Lisa M. Shewchuk, Liping Wang, Huizhen Zhao, Benjamin Schwartz, Joshua E. Cottom, Harvey E. Fries, Brian G. Lawhorn, Hu Li, Alan P. Graves, Hongwei Qi, Yongdong Zhao, Lara S. Kallander, Christopher Louer |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Purine Protein Conformation Administration Oral Protein Serine-Threonine Kinases Crystallography X-Ray Cell Line Rats Sprague-Dawley Structure-Activity Relationship chemistry.chemical_compound In vivo Drug Discovery Troponin I Animals Humans Structure–activity relationship Purine metabolism Sulfonamides MAP kinase kinase kinase Kinase MAP Kinase Kinase Kinases In vitro chemistry Biochemistry Purines Molecular Medicine Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry. 58:7431-7448 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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