%0 Journal Article
%A Lawhorn, Brian G.
%A Philp, Joanne
%A Zhao, Yongdong
%A Louer, Christopher
%A Hammond, Marlys
%A Cheung, Mui
%A Fries, Harvey
%A Graves, Alan P.
%A Shewchuk, Lisa
%A Wang, Liping
%A Cottom, Joshua
E.
%A Qi, Hongwei
%A Zhao, Huizhen
%A Totoritis, Rachel
%A Zhang, Guofeng
%A Schwartz, Benjamin
%A Li, Hu
%A Sweitzer, Sharon
%A Holt, Dennis
A.
%A Gatto, Gregory J.
%A Kallander, Lara S.
%D 2015
%T Identification
of Purines and 7‑Deazapurines
as Potent and Selective Type I Inhibitors of Troponin I‑Interacting
Kinase (TNNI3K)
%U https://acs.figshare.com/articles/journal_contribution/Identification_of_Purines_and_7_Deazapurines_as_Potent_and_Selective_Type_I_Inhibitors_of_Troponin_I_Interacting_Kinase_TNNI3K_/2128054
%R 10.1021/acs.jmedchem.5b00931.s001
%2 https://acs.figshare.com/ndownloader/files/3761857
%K novel heart failure medicines
%K bioavailable TNNI 3K inhibitors
%K TNNI 3K recognition
%K TNNI 3K
%K TNNI 3K inhibitors
%K TNNI 3K series
%X 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.
%I ACS Publications