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Synthesis and Structure–Activity Relationship Studies of 2‐(1,3,4‐Oxadiazole‐2(3 H )‐thione)‐3‐amino‐5‐arylthieno[2,3‐ b ]pyridines as Inhibitors of DRAK2
Author(s) -
Leonczak Piotr,
Gao LingJie,
Ramadori Anna Teresa,
Lescrinier Eveline,
Rozenski Jef,
De Jonghe Steven,
Herdewijn Piet
Publication year - 2014
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.201402234
Subject(s) - chemistry , drug discovery , selectivity , oxadiazole , ligand efficiency , benzothiophene , combinatorial chemistry , stereochemistry , kinase , chemical library , ligand (biochemistry) , small molecule , biochemistry , organic chemistry , receptor , catalysis , thiophene
In recent years, DAPK‐related apoptosis‐inducing protein kinase 2 (DRAK2) has emerged as a promising target for the treatment of a variety of autoimmune diseases and for the prevention of graft rejection after organ transplantation. However, medicinal chemistry optimization campaigns for the discovery of novel small‐molecule inhibitors of DRAK2 have not yet been published. Screening of a proprietary compound library led to the discovery of a benzothiophene analogue that displays an affinity constant ( K d ) value of 0.25 μ M . Variation of the core scaffold and of the substitution pattern afforded a series of 5‐arylthieno[2,3‐ b ]pyridines with strong binding affinity ( K d =0.008 μ M for the most potent representative). These compounds also show promising activity in a functional biochemical DRAK2 enzyme assay, with an IC 50 value of 0.029 μ M for the most potent congener. Selectivity profiling of the most potent compounds revealed that they lack selectivity within the DAPK family of kinases. However, one of the less potent analogues is a selective ligand for DRAK2 and can be used as starting point for the synthesis of selective and potent DRAK2 inhibitors.