title: Discovery of biaryl-4-carbonitriles as antihyperglycemic agents that may act through AMPK-p38 MAPK pathway.
abstract: A series of functionalized biaryl-4-carbonitriles was synthesized in three steps and evaluated for PTP-1B inhibitory activity. Among the synthesized compounds, four biaryls 6a-d showed inhibition (IC50 58-75 μM) against in vitro PTP-1B assay possibly due to interaction with amino acid residues Lys120, Tyr46 through hydrogen bonding and aromatic-aromatic interactions, respectively. Two biaryl-4-carbonitriles 6b and 6c showed improved glucose tolerance, fasting as well as postprandial blood glucose, serum total triglycerides, and increased high-density lipoprotein-cholesterol in SLM, STZ, STZ-S and C57BL/KsJ-db/db animal models. The bioanalysis of 4'-bromo-2,3-dimethyl-5-(piperidin-1-yl)biphenyl-4-carbonitrile (6b) revealed that like insulin, it increased 2-deoxyglucose uptake in skeletal muscle cells (L6 and C2C12 myotubes). The compound 6b significantly up-regulated the genes related to the insulin signaling pathways like AMPK, MAPK including glucose transporter-4 (GLUT-4) gene in muscle tissue of C57BL/KsJ-db/db mice. Furthermore, it was observed that the compound 6b up-regulated PPARα, UCP2 and HNF4α, which are key regulator of glucose, lipid, and fatty acid metabolism. Western blot analysis of the compound 6b showed that it significantly increased the phosphorylation of AMPK and p38 MAPK and ameliorated glucose uptake in C57BL/KsJ-db/db mice through the AMPK-p38 MAPK pathway.
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India. Electronic address: atul_goel@cdri.res.in.
authors.forename: Atul
authors.initials: A
authors.lastname: Goel
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Nag
authors.affiliation: Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Neha
authors.initials: N
authors.lastname: Rahuja
authors.affiliation: Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Rohit
authors.initials: R
authors.lastname: Srivastava
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Sumit
authors.initials: S
authors.lastname: Chaurasia
authors.affiliation: Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Sudeep
authors.initials: S
authors.lastname: Gautam
authors.affiliation: Division of Molecular and Structural Biology, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Sharat
authors.initials: S
authors.lastname: Chandra
authors.affiliation: Division of Molecular and Structural Biology, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Mohammad Imran
authors.initials: MI
authors.lastname: Siddiqi
authors.affiliation: Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Arvind K
authors.initials: AK
authors.lastname: Srivastava
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D008076:Cholesterol, HDL / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D006943:Hyperglycemia; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D018485:Muscle Fibers, Skeletal; D009570:Nitriles / Q000138:chemical synthesis / Q000494:pharmacology*; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013311:Streptozocin; D014280:Triglycerides / Q000097:blood; D000071246:Uncoupling Protein 2; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C000598029:40-bromo-2,3-dimethyl-5-(piperidin-1-yl)biphenyl-4-carbonitrile; D001786:Blood Glucose; D008076:Cholesterol, HDL; D051275:Glucose Transporter Type 4; D051557:Hepatocyte Nuclear Factor 4; C496594:Hnf4a protein, rat; D007004:Hypoglycemic Agents; D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; D009570:Nitriles; D047493:PPAR alpha; C495694:Slc2a4 protein, rat; D014280:Triglycerides; C000604390:Ucp2 protein, mouse; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; D013311:Streptozocin; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases
keywords: Anti-hyperglycemic activity; Biaryls; Gene expression; Glucose uptake; PTP1B