Rational design, synthesis, and structure–activity relationships of 5-amino-1H-pyrazole-4-carboxylic acid derivatives as protein tyrosine phosphatase 1B inhibitors

• Published in: Bioorganic & medicinal chemistry Vol. 25; no. 1; pp. 67 - 74
• Main Authors: Basu, Sujay, Prathipati, Philip, Thorat, Sachin, Ansari, Shariq, Patel, Meena, Jain, Vaibhav, Jinugu, Ramana R., Niranjan, Sanjay, De, Siddhartha, Reddy, Satyanarayana
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.01.2017; Elsevier
• Subjects: Amination; Biochemistry & Molecular Biology; Carboxylic Acids - chemistry; Carboxylic Acids - pharmacology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Drug Design; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Hydrophobic; Life Sciences & Biomedicine; Molecular Docking Simulation; Oxadiazole; Permeability; Pharmacology & Pharmacy; Pharmacophore; Physical Sciences; Protein tyrosine phosphatase 1B; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; Pyrazoles - chemistry; Pyrazoles - pharmacology; Science & Technology; Protein tyrosine phosphatase 1B; Oxadiazole; Permeability; Pharmacophore; Hydrophobic; PTP1B INHIBITORS; POTENT; OBESITY; COMPETITIVE INHIBITOR; DRUG DESIGN; PTP-1B INHIBITORS; DISCOVERY
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.10.012

[Display omitted] A series of novel amino-carboxylic based pyrazole as protein tyrosine phosphatase 1B (PTP1B) inhibitors were designed on the basis of structure-based pharmacophore model and molecular docking. Compounds containing different hydrophobic tail (1,2-diphenyl ethanone, oxdiadizole and dibenzyl amines) were synthesized and evaluated in PTP1B enzymatic assay. Structure–activity relationship based optimization resulted in identification of several potent, metabolically stable and cell permeable PTP1B inhibitors.