Design, synthesis, and SAR of new pyrrole-oxindole progesterone receptor modulators leading to 5-(7-Fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile (WAY-255348)
Design, synthesis, and SAR of new pyrrole-oxindole progesterone receptor modulators leading to 5-(7-Fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile (WAY-255348)
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DOI：
10.1021/jm701080t
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发表时间：
2008-03-27
影响因子：
7.3
通讯作者：
Wrobel, Jay E.
中科院分区：
文献类型：
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作者：
Fensome, Andrew;Adams, William R.;Wrobel, Jay E.
我们继续探索 3,3-二烷基-5-芳基吲哚系列黄体酮受体 (PR) 调节剂，寻找可用于女性保健的新药物：避孕、子宫肌瘤、子宫内膜异位症和某些乳腺癌。之前我们报道过该模板和相关模板的微妙结构变化会产生激动剂和拮抗剂特性之间的功能转换（Fensome et al. Biorg. Med. Chem. Lett. 2002, 12, 3487; 2003, 13, 1317）。我们在此报告了 5-(2-oxoindolin-5-yl)-1H-pyrrole-2-carbonitrile 类化合物中的新功能开关。我们发现3,3-二烷基取代基的大小对于控制功能响应很重要；因此，较小的基团（二甲基）提供有效的 PR 拮抗剂，而较大的基团（螺环己基）是 PR 激动剂。我们在细胞系统中的优化活动以及啮齿动物和非人灵长类动物的动力学特性的产物是 5-(7-氟-3,3二甲基-2-氧代-2,3-二氢-1H-吲哚-5-基)-1-甲基-1H-吡咯-2-甲腈 27 (WAY-255348)，该产品在大鼠和小鼠体内证明了对 PR 拮抗剂和避孕终点的有效和稳健的活性。食蟹猴和恒河猴，包括排卵抑制、月经诱导和生殖道形态。
We have continued to explore the 3,3-dialkyl-5-aryloxindole series of progesterone receptor (PR) modulators looking for new agents to be used in female healthcare: contraception, fibroids, endometriosis, and certain breast cancers. Previously we reported that subtle structural changes with this and related templates produced functional switches between agonist and antagonist properties (Fensome et al. Biorg. Med. Chem. Lett. 2002, 12, 3487; 2003, 13, 1317). We herein report a new functional switch within the 5-(2-oxoindolin-5-yl)-1H-pyrrole-2-carbonitrile class of compounds. We found that the size of the 3,3-dialkyl substituent is important for controlling the functional response; thus small groups (dimethyl) afford potent PR antagonists, whereas larger groups (spirocyclohexyl) are PR agonists. The product from our optimization activities in cell-based systems and also for kinetic properties in rodents and nonhuman primates was 5-(7-fluoro-3,3dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile 27 (WAY-255348), which demonstrated potent and robust activity on PR antagonist and contraceptive end points in the rat and also in cynomolgus and rhesus monkeys including ovulation inhibition, menses induction, and reproductive tract morphology.