Discovery of novel bromophenol 3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(isobutoxymethyl)benzyl)benzene-1,2-diol as protein tyrosine phosphatase 1B inhibitor and its anti-diabetic properties in C57BL/KsJ-db/db mice

• Published in: European journal of medicinal chemistry Vol. 64; pp. 129 - 136
• Main Authors: Jiang, Bo, Guo, Shuju, Shi, Dayong, Guo, Chao, Wang, Tao
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 01.06.2013; Elsevier
• Subjects: Animals; Anti-diabetic activities; Benzhydryl Compounds - chemical synthesis; Benzhydryl Compounds - chemistry; Benzhydryl Compounds - pharmacology; Bromophenol; Catechols - chemical synthesis; Catechols - chemistry; Catechols - pharmacology; Chemistry, Medicinal; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - enzymology; Diabetes Mellitus, Experimental - metabolism; Dose-Response Relationship, Drug; Drug Discovery; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Life Sciences & Biomedicine; Mice; Mice, Inbred C57BL; Mice, Obese; Molecular Structure; Pharmacology & Pharmacy; Protein tyrosine phosphatase 1B; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - metabolism; Science & Technology; Structure-Activity Relationship; Type 2 diabetes mellitus; T2DM; TCPTP; GLP-1; SGLT2; SAR; ASOs; TLC; Type 2 diabetes mellitus; SHP-1; Bromophenol; DPP4; TZDs; PTP1B; SHP-2; Anti-diabetic activities; TFAA; Protein tyrosine phosphatase 1B; TMS; LAR; HPLC; TARGET; OBESITY; GLUCOSE; INSULIN SENSITIVITY; CANCER
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2013.03.037

In an effort to develop novel small molecule PTP1B inhibitors, a series of bromophenol derivatives were designed, synthesized and evaluated in vitro and in vivo. All of the synthesized compounds displayed weak to potent PTP1B inhibitory activities (5.62–96.25%) at 20 μg/mL. Among these compounds, 3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(isobutoxymethyl)benzyl)benzene-1,2-diol (9) exhibited enhanced PTP1B inhibitory activity (IC50 = 1.50 μM) than the lead compound BDDPM (IC50 = 2.42 μM) and high selectivity against other PTPs (TCPTP, LAR, SHP-1 and SHP-2). Results of anti-diabetic assay using C57BL/KsJ-db/db mouse model demonstrated that compound 9 was effective at lowering blood glucose, total cholesterol and HbA1c (P < 0.01). [Display omitted] Novel bromophenol derivatives were designed, synthesized and evaluated as PTP1B inhibitors. •Bromophenol BDDPM was isolated from red alga Rhodomela confervoides.•Novel bromophenol derivatives were designed based on BDDPM.•The synthetic derivatives showed varying PTP1B inhibitory activities in vitro.•Compound 9 exhibits potent PTP1B inhibitory activity and high selectivity against other PTPs.•Compound 9 exhibits promising antidiabetic activities in db/db mouse model.