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)
| Autor: | Valerie Hudak, Zhiming Zhang, Yuan Zhu, Cheryl A. Mugford, Michael A. Marella, Thomas J. Berrodin, Kern Jeffrey Curtis, William R. Adams, Edward George Melenski, Matthew Yudt, Jeff Cohen, Richard C. Winneker, Ov D. Slayden, Andrea L. Adams, Andrew Fensome, Jay E. Wrobel, Puwen Zhang, Casey C. McComas, Arthur Illenberger, Christine Huselton |
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| Rok vydání: | 2008 |
| Předmět: |
Ovulation
Indoles Nitrile Stereochemistry Administration Oral Chemical synthesis chemistry.chemical_compound Structure-Activity Relationship Drug Discovery Progesterone receptor Tumor Cells Cultured Animals Humans Oxindole Pyrroles Pyrrole Bicyclic molecule Dose-Response Relationship Drug Molecular Structure Chemistry Stereoisomerism Alkaline Phosphatase Macaca mulatta female genital diseases and pregnancy complications Oxindoles Rats Macaca fascicularis Design synthesis Drug Design Lactam Molecular Medicine Female Receptors Progesterone |
| Zdroj: | Journal of medicinal chemistry. 51(6) |
| ISSN: | 0022-2623 |
| Popis: | 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)-1 H-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-3,3-dimethyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)-1-methyl-1 H-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. |
| Databáze: | OpenAIRE |
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