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)

Andrew Fensome, William R. Adams, Andrea L. Adams, Tom J. Berrodin, Jeff Cohen, Christine Huselton, Arthur Illenberger, Jeffrey C. Kern, Valerie A. Hudak, Michael A. Marella, Edward G. Melenski, Casey C. McComas, Cheryl A. Mugford, Ov D. Slayden, Matthew Yudt, Zhiming Zhang, Puwen Zhang, Yuan Zhu, Richard C. Winneker, Jay E. Wrobel

    Research output: Contribution to journalArticle

    165 Scopus citations

    Abstract

    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-3,3-dimethyl-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.

    Original languageEnglish (US)
    Pages (from-to)1861-1873
    Number of pages13
    JournalJournal of Medicinal Chemistry
    Volume51
    Issue number6
    DOIs
    StatePublished - Mar 27 2008

    ASJC Scopus subject areas

    • Molecular Medicine
    • Drug Discovery

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    Fensome, A., Adams, W. R., Adams, A. L., Berrodin, T. J., Cohen, J., Huselton, C., Illenberger, A., Kern, J. C., Hudak, V. A., Marella, M. A., Melenski, E. G., McComas, C. C., Mugford, C. A., Slayden, O. D., Yudt, M., Zhang, Z., Zhang, P., Zhu, Y., Winneker, R. C., & Wrobel, J. E. (2008). 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). Journal of Medicinal Chemistry, 51(6), 1861-1873. https://doi.org/10.1021/jm701080t