Discovery of biaryl-4-carbonitriles as antihyperglycemic agents that may act through AMPK-p38 MAPK pathway

• A series of functionalized biaryl-4-carbonitriles was synthesized.
• Four compounds exhibited in vitro PTP1B inhibitory activity.
• Two biaryls increased 2-deoxyglucose uptake in skeletal muscle cells.
• Biaryls showed blood glucose lowering activity in various in vivo animal models.
• Biaryls improved glucose uptake by phosphorylating the AMPK and p38 MAPK.

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.

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