Merck Research Laboratories, 2015 Galloping Hill Road, MS 2545, Kenilworth, NJ 07033-0539, USA.
Bioorg Med Chem Lett. 2012 Dec 1;22(23):7223-6. doi: 10.1016/j.bmcl.2012.09.048. Epub 2012 Oct 2.
High throughput screening identified the pyridothienopyrimidinone 1 as a ligand for the metabotropic glutamate receptor 1 (mGluR1=10 nM). Compound 1 has an excellent in vivo profile; however, it displays unfavorable pharmacokinetic issues and metabolic stability. Therefore, using 1 as a template, novel analogues (10i) were prepared. These analogues displayed improved oral exposure and activity in the Spinal Nerve Ligation (SNL) pain model.
高通量筛选发现吡啶并噻吩并嘧啶酮 1 是代谢型谷氨酸受体 1（mGluR1=10 nM）的配体。化合物 1 具有出色的体内特性；然而，它表现出不理想的药代动力学问题和代谢稳定性。因此，以 1 为模板，制备了新型类似物（10i）。这些类似物显示出在脊髓结扎（SNL）疼痛模型中改善的口服暴露和活性。
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