Department of Chemistry Research & Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
Bioorg Med Chem Lett. 2011 Apr 15;21(8):2460-7. doi: 10.1016/j.bmcl.2011.02.046. Epub 2011 Mar 15.
We discovered novel pyrrolidine MCHR1 antagonist 1 possessing moderate potency. Profiling of pyrrolidine 1 demonstrated that it was an inhibitor of the hERG channel. Investigation of the structure-activity relationship of this class of pyrrolidines allowed us to optimize the MCHR1 potency and decrease the hERG inhibition. Increasing the acidity of the amide proton by converting the benzamide in lead 1 to an anilide provided single digit nanomolar MCHR1 antagonists while replacing the dimethoxyphenyl ring of 1 with alkyl groups possessing increased polarity dramatically reduced the hERG inhibition.
我们发现了一种新型的吡咯烷 MCHR1 拮抗剂 1，它具有中等的效力。对吡咯烷 1 的特性分析表明，它是 hERG 通道的抑制剂。对这类吡咯烷的构效关系的研究使我们能够优化 MCHR1 的效力并降低 hERG 的抑制。通过将先导化合物 1 中的苯甲酰胺转化为酰苯胺，增加酰胺质子的酸性，得到了单位数纳摩尔的 MCHR1 拮抗剂，而用具有增加极性的烷基取代 1 的二甲氧基苯基环，则显著降低了 hERG 的抑制。
