Merck-Serono S.A., 9, Chemin des Mines, 1202 Geneva, Switzerland.
Bioorg Med Chem Lett. 2012 Sep 15;22(18):5909-14. doi: 10.1016/j.bmcl.2012.07.070. Epub 2012 Jul 31.
Indole-pyrrolidines were identified as inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) by high-throughput screening. Optimisation of the initial hit through structure-based design led to 7-azaindole-derivatives, with the best analogues displaying single digit nanomolar IC(50) potency. The modeling hypotheses were confirmed by solving the X-ray co-crystal structure of one of the lead compounds. These compounds were selective against 11β-hydroxysteroid dehydrogenase type 2 (selectivity ratio >200) and exhibited good inhibition of 11β-HSD1 (IC(50)<1μM) in a cellular model (3T3L1 adipocytes).
吲哚吡咯烷类化合物通过高通量筛选被鉴定为 11β-羟甾脱氢酶 1 型（11β-HSD1）的抑制剂。通过基于结构的设计对初始命中化合物进行优化，得到了 7-氮杂吲哚衍生物，其中最佳类似物的单数字纳摩尔 IC（50）效力。通过解析其中一种先导化合物的 X 射线共晶结构，验证了建模假设。这些化合物对 11β-羟甾脱氢酶 2 型（选择性比值>200）具有选择性，并且在细胞模型（3T3L1 脂肪细胞）中对 11β-HSD1 的抑制作用良好（IC（50）<1μM）。
