Novel 3-aryl indoles as progesterone receptor antagonists for uterine fibroids.

Richardson TI, Clarke CA, Yu KL, Yee YK, Bleisch TJ, Lopez JE, Jones SA, Hughes NE, Muehl BS, Lugar CW, Moore TL, Shetler PK, Zink RW, Osborne JJ, Montrose-Rafizadeh C, Patel N, Geiser AG, Galvin RJ, Dodge JA
ACS medicinal chemistry letters · 2011 · doi:10.1021/ml100220b · PMID:24900294 · PMC4017981
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Novel 3-aryl indoles were synthesized as potent, selective progesterone receptor antagonists that demonstrated oral activity and partial antagonism in rat uterus models, indicating potential for treating uterine fibroids.

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This study identifies novel 3-aryl indoles as potent antagonists of the human progesterone receptor, utilizing displacement and transcriptional activity assays in HEK293 cells to evaluate their binding affinity. The research highlights specific compounds with low nanomolar Ki values for the progesterone receptor while demonstrating varying degrees of selectivity against mineralocorticoid, glucocorticoid, and androgen receptors. A key limitation noted is the potential for off-target effects due to measurable, albeit weaker, interactions with these other steroid hormone receptors. Relevance to endometriosis: listed as one indication for GnRH antagonists, though the paper's main focus is uterine fibroids.

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Abstract

We report the synthesis and characterization of novel 3-aryl indoles as potent and efficacious progesterone receptor (PR) antagonists with potential for the treatment of uterine fibroids. These compounds demonstrated excellent selectivity over other steroid nuclear hormone receptors such as the mineralocorticoid receptor (MR). They were prepared from 2-bromo-6-nitro indole in four to six steps using a Suzuki cross-coupling as the key step. Compound 8f was orally active in the complement 3 model of progesterone antagonism in the rat uterus and demonstrated partial antagonism in the McPhail model of progesterone activity.
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[3H]methyltrienolone from human progesterone receptor expressed in HEK293 cellsMore data for this Ligand-Target Pair Affinity DataKi: 0.834nMAssay Description:Displacement of [3H]methyltrienolone from human progesterone receptor expressed in HEK293 cellsMore data for this Ligand-Target Pair Affinity DataKi: 1.45nMAssay Description:Displacement of [3H]methyltrienolone from human progesterone receptor expressed in HEK293 cellsMore data for this Ligand-Target Pair Affinity DataKi: 1.51nMAssay Description:Displacement of [3H]methyltrienolone from human mineralocorticoid receptor expressed in HEK293 cellsMore data for this Ligand-Target Pair Affinity DataIC50: 2.29nMAssay Description:Antagonist activity at human progesterone receptor expressed in HEK293 cells assessed as inhibition of R5050-induced transcriptional activity by GRE-...More data for this Ligand-Target Pair Affinity DataIC50: 3.38nMAssay Description:Antagonist activity at human progesterone receptor expressed in HEK293 cells 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R5050-induced transcriptional activity by...More data for this Ligand-Target Pair Affinity DataKi: 403nMAssay Description:Displacement of [3H]methyltrienolone from human androgen receptor expressed in HEK293 cellsMore data for this Ligand-Target Pair Affinity DataKi: 454nMAssay Description:Displacement of [3H]methyltrienolone from human progesterone receptor expressed in HEK293 cellsMore data for this Ligand-Target Pair Affinity DataKi: 464nMAssay Description:Displacement of [3H]methyltrienolone from human progesterone receptor expressed in HEK293 cellsMore data for this Ligand-Target Pair Affinity DataKi: 478nMAssay Description:Displacement of [3H]methyltrienolone from human progesterone receptor expressed in HEK293 cellsMore data for this Ligand-Target Pair Affinity DataIC50: 485nMAssay Description:Antagonist activity at human progesterone receptor expressed in HEK293 cells assessed as inhibition of R5050-induced transcriptional activity by GRE-...More data for this Ligand-Target Pair Affinity DataKi: 490nMAssay Description:Displacement of [3H]methyltrienolone from human androgen receptor expressed in HEK293 cellsMore data for this Ligand-Target Pair Affinity DataKi: 523nMAssay Description:Displacement of [3H]methyltrienolone from human glucocorticoid receptor expressed in HEK293 cellsMore data for this Ligand-Target Pair Affinity DataKi: 648nMAssay Description:Displacement of [3H]methyltrienolone from human androgen receptor expressed in HEK293 cellsMore data for this Ligand-Target Pair Affinity DataKi: 676nMAssay Description:Displacement of [3H]methyltrienolone from human androgen receptor expressed in HEK293 cellsMore data for this Ligand-Target Pair Affinity DataIC50: 715nMAssay Description:Antagonist activity at human progesterone receptor expressed in HEK293 cells assessed as inhibition of R5050-induced transcriptional activity by GRE-...More data for this Ligand-Target Pair Affinity DataIC50: 765nMAssay Description:Antagonist activity at human progesterone receptor expressed in HEK293 cells assessed as inhibition of R5050-induced transcriptional activity by GRE-...More data for this Ligand-Target Pair Affinity DataKi: 780nMAssay Description:Displacement of [3H]methyltrienolone from human glucocorticoid receptor expressed in HEK293 cellsMore data for this Ligand-Target Pair Affinity DataKi: 849nMAssay Description:Displacement of [3H]methyltrienolone from human mineralocorticoid receptor expressed in HEK293 cellsMore data for this Ligand-Target Pair Affinity DataKi: 927nMAssay Description:Displacement of [3H]methyltrienolone from human glucocorticoid receptor expressed in HEK293 cellsMore data for this Ligand-Target Pair Affinity DataKi: 977nMAssay Description:Displacement of [3H]methyltrienolone from human glucocorticoid receptor expressed in HEK293 cellsMore data for this Ligand-Target Pair Affinity DataKi: 1.00E+3nMAssay Description:Displacement of [3H]methyltrienolone from human mineralocorticoid receptor expressed in HEK293 cellsMore data for this Ligand-Target Pair Affinity DataKi: 1.23E+3nMAssay Description:Displacement of [3H]methyltrienolone from human progesterone receptor expressed in HEK293 cellsMore data for this Ligand-Target Pair Affinity DataKi: 1.39E+3nMAssay Description:Displacement of [3H]methyltrienolone from human mineralocorticoid receptor expressed in HEK293 cellsMore data for this Ligand-Target Pair Affinity DataKi: 1.44E+3nMAssay Description:Displacement of [3H]methyltrienolone from human mineralocorticoid receptor expressed in HEK293 cellsMore data for this Ligand-Target Pair

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