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, Fensome A, William R Adams, Adams WR, Andrea L Adams, Adams AL, Tom J Berrodin, Berrodin TJ, Jeff Cohen, Cohen J, Christine Huselton, Huselton C, Illenberger A, Arthur Illenberger, Jeffrey C Kern, Kern JC, Hudak VA, Valerie A Hudak, Michael A Marella, Marella MA, Melenski EG, Edward G Melenski, Casey C McComas, McComas CC, Mugford CA, Cheryl A Mugford, Ov D. Slayden, Slayden OD, Matthew Yudt, Yudt M, Zhiming Zhang, Zhang Z, Puwen Zhang, Zhang P, Zhu Y, Yuan Zhu, Winneker RC, Richard C. Winneker, Wrobel JE, Jay E Wrobel
Journal of medicinal chemistry · 2008 · doi:10.1021/jm701080t · PMID:18318463
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This study synthesized pyrrole-oxindole derivatives and identified WAY-255348 as a potent progesterone receptor antagonist with contraceptive effects in preclinical models.

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The paper reports the design, synthesis, and structure–activity relationship of new pyrrole-oxindole progesterone receptor (PR) modulators, culminating in compounds including 5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile (WAY-255348). PR activity was assessed in human T47D cells using alkaline phosphatase readouts for agonist (EC50 values) and antagonist effects (IC50 values), and PR ligand binding was also measured by displacement of [3H]R5020; reported potency values span from sub-nanomolar levels for some measures to tens of nanomolar or higher for others. The compounds were also profiled for cross-reactivity against other steroid receptors including glucocorticoid receptor (GR) and androgen receptor (AR), with additional mention of mineralocorticoid receptor (MR), indicating variable selectivity. The study’s primary caveat, as presented here, is that the provided text is dominated by assay potency listings without accompanying synthesis details, SAR rationale, or mechanistic/phenotypic validation beyond PR/other receptor cell-based assays; This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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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.
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Report error Found 53 Enz. Inhib. hit(s) with all data for entry = 50038396 Affinity DataEC50: 0.150nMAssay Description:Agonist activity at human PR expressed in human T47D cells assessed as stimulation of alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 0.200nMAssay Description:Antagonist activity at human PR expressed in human T47D cells assessed as inhibition of progesterone induced alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 0.5nMAssay Description:Displacement of [3H]R5020 from human PR in human T47D cells by whole cell assayMore data for this Ligand-Target Pair Affinity DataIC50: 0.600nMAssay Description:Displacement of [3H]R5020 from human PR in human T47D cells by whole cell assayMore data for this Ligand-Target Pair Affinity DataIC50: 0.600nMAssay Description:Antagonist activity at human GR ligand binding domain expressed in african green monkey COS7 cells in presence of Dexamethasone by Gal4 hybrid assayMore data for this Ligand-Target Pair Affinity DataEC50: 1.10nMAssay Description:Agonist activity at human PR expressed in human T47D cells assessed as stimulation of alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataEC50: 1.30nMAssay Description:Agonist activity at human PR expressed in human T47D cells assessed as stimulation of alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataEC50: 2nMAssay Description:Agonist activity at human PR expressed in human T47D cells assessed as stimulation of alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataEC50: 2.30nMAssay Description:Agonist activity at human PR expressed in human T47D cells assessed as stimulation of alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 3.20nMAssay Description:Antagonist activity at human PR expressed in human T47D cells assessed as inhibition of progesterone induced alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 3.30nMAssay Description:Displacement of [3H]R5020 from human PR in human T47D cells by whole cell assayMore data for this Ligand-Target Pair Affinity DataIC50: 3.30nMAssay Description:Antagonist activity at human PR expressed in human T47D cells assessed as inhibition of progesterone induced alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 3.60nMAssay Description:Displacement of [3H]R5020 from human PR in human T47D cells by whole cell assayMore data for this Ligand-Target Pair Affinity DataIC50: 4.10nMAssay Description:Displacement of [3H]R5020 from human PR in human T47D cells by whole cell assayMore data for this Ligand-Target Pair Affinity DataIC50: 4.5nMAssay Description:Antagonist activity at human PR expressed in human T47D cells assessed as inhibition of progesterone induced alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 4.90nMAssay Description:Antagonist activity at human PR expressed in human T47D cells assessed as inhibition of progesterone induced alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 4.90nMAssay Description:Displacement of [3H]R5020 from human PR in human T47D cells by whole cell assayMore data for this Ligand-Target Pair Affinity DataIC50: 5nMAssay Description:Antagonist activity at human PR expressed in human T47D cells assessed as inhibition of progesterone induced alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 5.5nMAssay Description:Displacement of [3H]R5020 from human PR in human T47D cells by whole cell assayMore data for this Ligand-Target Pair Affinity DataIC50: 5.90nMAssay Description:Antagonist activity at human PR expressed in human T47D cells assessed as inhibition of progesterone induced alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 6.10nMAssay Description:Antagonist activity at human AR ligand binding domain expressed in african green monkey COS7 cells in presence of 5-alpha-dihydrotestosterone by Gal4...More data for this Ligand-Target Pair Affinity DataIC50: 6.90nMAssay Description:Antagonist activity at human AR ligand binding domain expressed in african green monkey COS7 cells in presence of 5-alpha-dihydrotestosterone by Gal4...More data for this Ligand-Target Pair Affinity DataIC50: 8.10nMAssay Description:Displacement of [3H]R5020 from human PR in human T47D cells by whole cell assayMore data for this Ligand-Target Pair Affinity DataIC50: 10nMAssay Description:Antagonist activity at human PR expressed in human T47D cells assessed as inhibition of progesterone induced alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 13nMAssay Description:Antagonist activity at human PR expressed in human T47D cells assessed as inhibition of progesterone induced alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 14.7nMAssay Description:Displacement of [3H]R5020 from human PR in human T47D cells by whole cell assayMore data for this Ligand-Target Pair Affinity DataIC50: 15nMAssay Description:Antagonist activity at human PR expressed in human T47D cells assessed as inhibition of progesterone induced alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 15nMAssay Description:Antagonist activity at human PR expressed in human T47D cells assessed as inhibition of progesterone induced alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 20nMAssay Description:Antagonist activity at human PR expressed in human T47D cells assessed as inhibition of progesterone induced alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 20.3nMAssay Description:Antagonist activity at human PR expressed in human T47D cells assessed as inhibition of progesterone induced alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 22nMAssay Description:Displacement of [3H]R5020 from human PR in human T47D cells by whole cell assayMore data for this Ligand-Target Pair Affinity DataIC50: 25nMAssay Description:Antagonist activity at human PR expressed in human T47D cells assessed as inhibition of progesterone induced alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 25nMAssay Description:Displacement of [3H]R5020 from human PR in human T47D cells by whole cell assayMore data for this Ligand-Target Pair Affinity DataIC50: 27nMAssay Description:Antagonist activity at human PR expressed in human T47D cells assessed as inhibition of progesterone induced alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 27nMAssay Description:Antagonist activity at human PR expressed in human T47D cells assessed as inhibition of progesterone induced alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 29nMAssay Description:Antagonist activity at human PR expressed in human T47D cells assessed as inhibition of progesterone induced alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 30nMAssay Description:Antagonist activity at human PR expressed in human T47D cells assessed as inhibition of progesterone induced alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 30nMAssay Description:Antagonist activity at human PR expressed in human T47D cells assessed as inhibition of progesterone induced alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 30nMAssay Description:Antagonist activity at human PR expressed in human T47D cells assessed as inhibition of progesterone induced alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 36nMAssay Description:Displacement of [3H]R5020 from human PR in human T47D cells by whole cell assayMore data for this Ligand-Target Pair Affinity DataIC50: 48nMAssay Description:Antagonist activity at human PR expressed in human T47D cells assessed as inhibition of progesterone induced alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 80nMAssay Description:Displacement of [3H]R5020 from human PR in human T47D cells by whole cell assayMore data for this Ligand-Target Pair Affinity DataIC50: 85nMAssay Description:Antagonist activity at human GR ligand binding domain expressed in african green monkey COS7 cells in presence of Dexamethasone by Gal4 hybrid assayMore data for this Ligand-Target Pair Affinity DataIC50: 164nMAssay Description:Antagonist activity at human PR expressed in human T47D cells assessed as inhibition of progesterone induced alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 194nMAssay Description:Antagonist activity at human PR expressed in human T47D cells assessed as inhibition of progesterone induced alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 196nMAssay Description:Antagonist activity at human AR ligand binding domain expressed in african green monkey COS7 cells in presence of 5-alpha-dihydrotestosterone by Gal4...More data for this Ligand-Target Pair Affinity DataEC50: 300nMAssay Description:Agonist activity at human PR expressed in human T47D cells assessed as stimulation of alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 300nMAssay Description:Antagonist activity at human PR expressed in human T47D cells assessed as inhibition of progesterone induced alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 351nMAssay Description:Antagonist activity at human PR expressed in human T47D cells assessed as inhibition of progesterone induced alkaline phosphataseMore data for this Ligand-Target Pair Affinity DataIC50: 1.60E+3nMAssay Description:Antagonist activity at human MR ligand binding domain expressed in african green monkey COS7 cells in presence of aldosterone by Gal4 hybrid assayMore data for this Ligand-Target Pair

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Condition tags

endometriosis

MeSH descriptors

Drug Design Indoles Indoles Indoles Pyrroles Receptors, Progesterone Administration, Oral Alkaline Phosphatase Alkaline Phosphatase Animals Dose-Response Relationship, Drug Female Humans Indoles Macaca fascicularis Macaca mulatta Molecular Structure Ovulation Ovulation Oxindoles

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