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-c arbonitrile (WAY-255348).

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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 OD, Yudt M, Zhang Z, Zhang P, Zhu Y, Winneker RC, Wrobel JE

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-c arbonitrile (WAY-255348).

J Med Chem. 2008 Mar 27;51(6):1861-73. doi: 10.1021/jm701080t. Epub 2008 Mar 5.

PubMed ID
18318463 [ View in PubMed
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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)-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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
MifepristoneGlucocorticoid receptorIC 50 (nM)0.6N/AN/ADetails
MifepristoneProgesterone receptorIC 50 (nM)0.2N/AN/ADetails
MifepristoneProgesterone receptorIC 50 (nM)0.6N/AN/ADetails
TanaprogetProgesterone receptorIC 50 (nM)0.5N/AN/ADetails
TanaprogetProgesterone receptorEC 50 (nM)0.15N/AN/ADetails