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 Slayden, Matthew Yudt, Zhiming Zhang, Puwen Zhang, Yuan Zhu, Richard C. Winneker, Jay E. Wrobel

    Research output: Contribution to journalArticle

    160 Citations (Scopus)

    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

    Fingerprint

    Pyrroles
    Progesterone Receptors
    Modulators
    Ovulation Inhibition
    Switches
    Macaca fascicularis
    Menstruation
    Leiomyoma
    Endometriosis
    Contraceptive Agents
    Macaca mulatta
    Contraception
    Primates
    Rats
    Rodentia
    Breast Neoplasms
    Delivery of Health Care
    Kinetics
    oxindole
    5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile

    ASJC Scopus subject areas

    • Organic Chemistry

    Cite this

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

    In: Journal of Medicinal Chemistry, Vol. 51, No. 6, 27.03.2008, p. 1861-1873.

    Research output: Contribution to journalArticle

    Fensome, A, Adams, WR, Adams, AL, Berrodin, TJ, Cohen, J, Huselton, C, Illenberger, A, Kern, JC, Hudak, VA, Marella, MA, Melenski, EG, McComas, CC, Mugford, CA, Slayden, O, Yudt, M, Zhang, Z, Zhang, P, Zhu, Y, Winneker, RC & Wrobel, JE 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, vol. 51, no. 6, pp. 1861-1873. https://doi.org/10.1021/jm701080t
    Fensome, Andrew ; Adams, William R. ; Adams, Andrea L. ; Berrodin, Tom J. ; Cohen, Jeff ; Huselton, Christine ; Illenberger, Arthur ; Kern, Jeffrey C. ; Hudak, Valerie A. ; Marella, Michael A. ; Melenski, Edward G. ; McComas, Casey C. ; Mugford, Cheryl A. ; Slayden, Ov ; Yudt, Matthew ; Zhang, Zhiming ; Zhang, Puwen ; Zhu, Yuan ; Winneker, Richard C. ; Wrobel, Jay E. / 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). In: Journal of Medicinal Chemistry. 2008 ; Vol. 51, No. 6. pp. 1861-1873.
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    AU - Adams, William R.

    AU - Adams, Andrea L.

    AU - Berrodin, Tom J.

    AU - Cohen, Jeff

    AU - Huselton, Christine

    AU - Illenberger, Arthur

    AU - Kern, Jeffrey C.

    AU - Hudak, Valerie A.

    AU - Marella, Michael A.

    AU - Melenski, Edward G.

    AU - McComas, Casey C.

    AU - Mugford, Cheryl A.

    AU - Slayden, Ov

    AU - Yudt, Matthew

    AU - Zhang, Zhiming

    AU - Zhang, Puwen

    AU - Zhu, Yuan

    AU - Winneker, Richard C.

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