Synthesis and biological evaluation of 4,4-dimethyl lithocholic acid derivatives as novel inhibitors of protein tyrosine phosphatase 1B.
Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator of both insulin and leptin signals. For years, inhibiting of PTP1B has been considered to be a potential therapeutics for treating Type 2 diabetes and obesity. Recently, we recognized lithocholic acid (LCA) as a natural inhibitor against PTP1B (IC(50)=12.74 μM) by a vertical screen for the first time. Further SAR research was carried out by synthesizing and evaluating a series of compounds bearing two methyls at C-4 position and a fused heterocycle to ring A. Among them, compound 14b achieved a PTP1B inhibitory activity about eightfold than LCA and a 14-fold selectivity over the homogenous enzyme TCPTP.
Shanghai Engineering Research Center of Molecular Theraputics and New Drug Development, East China Normal University, Shanghai 200062, China.
Hai-Bing
HB
He
Li-Xin
LX
Gao
Qi-Feng
QF
Deng
Wei-Ping
WP
Ma
Chun-Lan
CL
Tang
Wen-Wei
WW
Qiu
Jie
J
Tang
Jing-Ya
JY
Li
Jia
J
Li
Fan
F
Yang
D001665:Binding Sites; D020134:Catalytic Domain; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D007700:Kinetics; D008095:Lithocholic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D062105:Molecular Docking Simulation; D009765:Obesity / Q000188:drug therapy; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D008095:Lithocholic Acid; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1