Synthesis and biological evaluation of 4,4-dimethyl lithocholic acid derivatives as novel inhibitors of protein tyrosine phosphatase 1B
- Resource Type
- Authors
- Wen-Wei Qiu; Wei-Ping Ma; Li-Xin Gao; Hai-Bing He; Qi-Feng Deng; Jia Li; Fan Yang; Jing-Ya Li; Jie Tang; Chun-Lan Tang
- Source
- Bioorganic & Medicinal Chemistry Letters. 22:7237-7242
- Subject
- Lithocholic acid
Stereochemistry
medicine.medical_treatment
Clinical Biochemistry
Pharmaceutical Science
Protein tyrosine phosphatase
Biochemistry
Structure-Activity Relationship
chemistry.chemical_compound
Catalytic Domain
Drug Discovery
medicine
Humans
Structure–activity relationship
Obesity
Enzyme Inhibitors
Binding site
Molecular Biology
Protein Tyrosine Phosphatase, Non-Receptor Type 1
chemistry.chemical_classification
Binding Sites
Leptin
Insulin
Organic Chemistry
Molecular Docking Simulation
Kinetics
Enzyme
Diabetes Mellitus, Type 2
chemistry
Molecular Medicine
Lithocholic Acid
Selectivity
hormones, hormone substitutes, and hormone antagonists
- Language
- ISSN
- 0960-894X
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.