TY - JOUR
T1 - Chiral disubstituted piperidinyl ureas
T2 - a class of dual diacylglycerol lipase-α and ABHD6 inhibitors
AU - Deng, Hui
AU - van der Wel, Tom
AU - van den Berg, Richard J B H N
AU - van den Nieuwendijk, Adrianus M C H
AU - Janssen, Freek J
AU - Baggelaar, Marc P
AU - Overkleeft, Hermen S
AU - van der Stelt, Mario
PY - 2017/5/1
Y1 - 2017/5/1
N2 - Inhibitors of diacylglycerol lipases and α,β-hydrolase domain containing protein 6 (ABHD6) are potential leads for the development of therapeutic agents for metabolic and neurodegenerative disorders. Here, we report the enantioselective synthesis and structure activity relationships of triazole ureas featuring chiral, hydroxylated 2-benzylpiperidines as dual inhibitors of DAGLα and ABHD6. The chirality of the carbon bearing the C2 substituent, as well as the position of the hydroxyl (tolerated at C5, but not at C3) has profound influence on the inhibitory activity of both DAGLα and ABHD6, as established using biochemical assays and competitive activity-based protein profiling on mouse brain extracts.
AB - Inhibitors of diacylglycerol lipases and α,β-hydrolase domain containing protein 6 (ABHD6) are potential leads for the development of therapeutic agents for metabolic and neurodegenerative disorders. Here, we report the enantioselective synthesis and structure activity relationships of triazole ureas featuring chiral, hydroxylated 2-benzylpiperidines as dual inhibitors of DAGLα and ABHD6. The chirality of the carbon bearing the C2 substituent, as well as the position of the hydroxyl (tolerated at C5, but not at C3) has profound influence on the inhibitory activity of both DAGLα and ABHD6, as established using biochemical assays and competitive activity-based protein profiling on mouse brain extracts.
U2 - 10.1039/c7md00029d
DO - 10.1039/c7md00029d
M3 - Article
C2 - 30108813
SN - 2040-2503
VL - 8
SP - 982
EP - 988
JO - MedChemComm
JF - MedChemComm
IS - 5
ER -