发现和评价作为神经肽 Y5 受体拮抗剂的螺环衍生物。
Discovery and evaluation of spirocyclic derivatives as antagonists of the neuropeptide Y5 receptor.
机构信息
Department of Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics, Groton, CT 06340, USA.
出版信息
Bioorg Med Chem Lett. 2012 Apr 15;22(8):2738-43. doi: 10.1016/j.bmcl.2012.02.098. Epub 2012 Mar 6.
A novel series of spirocyclic derivatives was synthesized and evaluated as NPY Y5R antagonists for the treatment of obesity. Cis and trans analogs 7a and 8a were equipotent in a Y5R binding assay (K(i)'s ≤ 1 nM) and displayed good stability in human and rat liver microsome preparations. Compound 7a failed to demonstrate weight loss activity in a diet-induced obese (DIO) rat model at unbound drug levels in the brain that exceeded the Y5R K(i) value by 25-fold over a 24-h time-period.
合成了一系列新型的螺环衍生物，并将其作为 NPY Y5R 拮抗剂进行评估，用于治疗肥胖症。顺式和反式类似物 7a 和 8a 在 Y5R 结合测定中具有相同的效力（K(i)值≤1 nM），并且在人肝微粒体和大鼠肝微粒体制剂中具有良好的稳定性。在未结合药物水平下，化合物 7a 在饮食诱导肥胖（DIO）大鼠模型中未能显示出减肥活性，在 24 小时的时间内，脑中的未结合药物水平超过 Y5R K(i)值 25 倍。
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