Department of Chemistry, Metabolic Pathways Centre for Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, USA.
Bioorg Med Chem Lett. 2010 Jan 1;20(1):371-4. doi: 10.1016/j.bmcl.2009.10.092. Epub 2009 Oct 25.
The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.
先前报道的吡咯烷类孕激素受体部分激动剂具有优异的效力，但存在严重的缺陷，包括 hERG 阻断和在大鼠中的高分布体积。将基本的吡咯烷胺有意转化为磺酰胺、氨基甲酸酯或酰胺，以解决这些缺陷。本文披露了这些非碱性吡咯烷衍生物的部分激动活性程度的评估，并展示了它们在子宫内膜异位症的体内模型中的疗效。
