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A novel series of thiophene‐containing biaryl amide glucagon receptor (GCGR) antagonists were designed and synthesized. Two compounds of this series, 14f and 14h, exhibited good GCGR binding (IC50 = 6.1 and 4.4 μm, respectively) and cAMP functional activities (IC50 = 4.4 and 14.4 μm, respectively). The possible binding modes of compounds 14f and 14h with GCGR were explored by molecular simulation.
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