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Probing 2 H ‐Indazoles as Templates for SGK1, Tie2, and SRC Kinase Inhibitors
Author(s) -
Schoene Jens,
Gazzi Thais,
Lindemann Peter,
Christmann Mathias,
Volkamer Andrea,
Nazaré Marc
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900328
Subject(s) - indazole , docking (animal) , kinase , in silico , chemistry , computational biology , combinatorial chemistry , stereochemistry , biochemistry , biology , medicine , nursing , gene
The broader and systematic application of a novel scaffold is often hampered by the unavailability of a short and reliable synthetic access. We investigated a new strategy for the design and synthesis of an array of N2‐substituted aza‐2 H ‐indazole derivatives as potential kinase inhibitors. Guided by a rational ligand alignment approach to qualify the so‐far underrepresented aza‐2 H ‐indazole scaffold, indazoles were connected at the N2 position with a phenyl spacer and an arylsulfonamide or amide linkage. Initial profiling against a panel of 30 kinases confirmed the in silico predicted selectivity bias. A synthesized focused library of 52 different aza‐2 H ‐indazole derivatives showed good initial selective inhibition against SGK1, Tie2, and SRC kinases, with the best representatives having IC 50 values in the range of 500 n m . In a comparative computational study, these data were analyzed and rationalized in light of docking studies.