Improving the developability profile of pyrrolidine progesterone receptor partial agonists

Lara S Kallander, David G Washburn, Tram H Hoang, James S Frazee, Patrick Stoy, Latisha Johnson, Qing Lu, Marlys Hammond, Linda S Barton, Jaclyn R Patterson, Leonard M Azzarano, Rakesh Nagilla, Kevin P Madauss, Shawn P Williams, Eugene L Stewart, Chaya Duraiswami, Eugene T Grygielko, Xiaoping Xu, Nicholas J Laping, Jeffrey D Bray, Scott K Thompson
Bioorganic & medicinal chemistry letters · 2010 · doi:10.1016/j.bmcl.2009.10.092 · PMID:19926282
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⚙ AI-generated summary by claude@2026-06, 2026-06-13 ⓘ

Pyrrolidine progesterone receptor partial agonists were modified from basic amines to non-basic sulfonamides, carbamates, or amides to improve developability, and these derivatives showed partial agonism and in vivo efficacy for endometriosis.

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The paper focuses on improving the developability profile of pyrrolidine progesterone receptor (PR) partial agonists by characterizing their agonist activity at the PR using human T47D cells. Across a range of measured EC50 values reported in the study (e.g., approximately 0.1 nM to 75 nM), the compounds show variable PR agonist potency in this cell-based assay. A key limitation is that the provided text only includes PR functional potency readouts without additional developability metrics or broader experimental context. The 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

The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.
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Report error Found 136 Enz. Inhib. hit(s) with all data for entry = 50030995 Affinity DataEC50: 0.100nMAssay Description:Agonist activity at PR in human T47D cellsMore data for this Ligand-Target Pair Affinity DataEC50: 0.400nMAssay Description:Agonist activity at PR in human T47D cellsMore data for this Ligand-Target Pair Affinity DataEC50: 1nMAssay Description:Agonist activity at PR in human T47D cellsMore data for this Ligand-Target Pair Affinity DataEC50: 2.10nMAssay Description:Agonist activity at PR in human T47D cellsMore data for this Ligand-Target Pair Affinity DataEC50: 3nMAssay Description:Agonist activity at PR in human T47D cellsMore data for this Ligand-Target Pair Affinity DataEC50: 3nMAssay Description:Agonist activity at PR in human T47D cellsMore data for this Ligand-Target Pair Affinity DataEC50: 4nMAssay Description:Agonist activity at PR in human T47D cellsMore data for this Ligand-Target Pair Affinity DataEC50: 8nMAssay Description:Agonist activity at PR in human T47D cellsMore data for this Ligand-Target Pair Affinity DataEC50: 9nMAssay Description:Agonist activity at PR in human T47D cellsMore data for this Ligand-Target Pair Affinity DataEC50: 10nMAssay Description:Agonist activity at PR in human T47D cellsMore data for this Ligand-Target Pair Affinity DataEC50: 11nMAssay Description:Agonist activity at PR in human T47D cellsMore data for this Ligand-Target Pair Affinity DataEC50: 24nMAssay Description:Agonist activity at PR in human T47D cellsMore data for this Ligand-Target Pair Affinity DataEC50: 25nMAssay Description:Agonist activity at PR in human T47D cellsMore data for this Ligand-Target Pair Affinity DataEC50: 35nMAssay Description:Agonist activity at PR in human T47D cellsMore data for this Ligand-Target Pair Affinity DataEC50: 36nMAssay Description:Agonist activity at PR in human T47D cellsMore data for this Ligand-Target Pair Affinity DataEC50: 41nMAssay Description:Agonist activity at PR in human T47D cellsMore data for this Ligand-Target Pair Affinity DataEC50: 75nMAssay Description:Agonist activity at PR in human T47D cellsMore data for this Ligand-Target Pair

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Condition tags

endometriosis

MeSH descriptors

Pyrrolidines Receptors, Progesterone Animals Binding Sites Carbamates Carbamates Crystallography, X-Ray Endometriosis Endometriosis ERG1 Potassium Channel Ether-A-Go-Go Potassium Channels Ether-A-Go-Go Potassium Channels Female Humans Pyrrolidines Pyrrolidines Pyrrolidines Rats Receptors, Progesterone Receptors, Progesterone

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europepmc
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pubmed
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