Discovery and optimization of pyridyl-cycloalkyl-carboxylic acids as inhibitors of microsomal prostaglandin E synthase-1 for the treatment of endometriosis

Marcus Koppitz, Koppitz M, Bräuer N, Nico Bräuer, Antonius ter Laak, Horst Irlbacher, Irlbacher H, Rotgeri A, Andrea Rotgeri, Anne-Marie Coelho, Coelho AM, Daryl Walter, Daryl S. Walter, Walter D, Andreas Steinmeyer, Steinmeyer A, Zollner TM, Thomas M. Zollner, Michaele Peters, Peters M, Jens Nagel
Bioorganic & medicinal chemistry letters · 2019 · vol. 29(18) , pp. 2700–2705 · doi:10.1016/j.bmcl.2019.07.007 · PMID:31362919 · W2964053441
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⚙ AI-generated summary by gemini-2.5-flash-lite+body, 2026-06-08 ⓘ

Pyridyl-cycloalkyl-carboxylic acids were discovered and optimized as inhibitors of microsomal prostaglandin E synthase-1, with several compounds exhibiting low nanomolar IC50 values.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-08 · read from full text ⓘ

The paper reports the discovery and optimization of pyridyl-cycloalkyl-carboxylic acid compounds as inhibitors of microsomal prostaglandin E synthase-1 (PTGES1), using biochemical inhibition assays with human recombinant FLAG-tagged PTGES expressed in baculovirus-infected Hi-5 insect cells and prostaglandin H2 as the substrate. Across many ligand–target pairs, the reported IC50 values span from low nanomolar to micromolar range, with multiple compounds showing potency in the ~10–100 nM range in the human enzyme format. A major caveat explicitly reflected in the provided text is that the data are in vitro enzymatic assay results using recombinant protein expression systems (including Hi-5 cells and separate mouse/human recombinant PTGES constructs), rather than endometriosis-specific biological or clinical evidence. This paper is centrally about endometriosis — it focuses on PTGES1 inhibition for the treatment of endometriosis.

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Abstract

Here we report on novel and potent pyridyl-cycloalkyl-carboxylic acid inhibitors of microsomal prostaglandin E synthase-1 (PTGES). PTGES produces, as part of the prostaglandin pathway, prostaglandin E2 which is a well-known driver for pain and inflammation. This fact together with the observed upregulation of PTGES during inflammation suggests that blockade of the enzyme might provide a beneficial treatment option for inflammation related conditions such as endometriosis. Compound 5a, a close analogue of the screening hit, potently inhibited PTGES in vitro, displayed excellent PK properties in vitro and in vivo and demonstrated efficacy in a CFA-induced pain model in mice and in a rat dyspareunia endometriosis model and was therefore selected for further studies.
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Description:Inhibition of mouse recombinant FLAG-tagged PTGES expressed in baculovirus infected Hi-5 insect cells using prostaglandin H2 as substrate incubated f...More data for this Ligand-Target Pair Affinity DataIC50: 670nMAssay Description:Inhibition of human PTGESMore data for this Ligand-Target Pair Affinity DataIC50: 752nMAssay Description:Inhibition of human recombinant FLAG-tagged PTGES expressed in baculovirus infected Hi-5 insect cells using prostaglandin H2 as substrate preincubate...More data for this Ligand-Target Pair Affinity DataIC50: 765nMAssay Description:Inhibition of mouse recombinant FLAG-tagged PTGES expressed in baculovirus infected Hi-5 insect cells using prostaglandin H2 as substrate incubated f...More data for this Ligand-Target Pair Affinity DataIC50: 818nMAssay Description:Inhibition of mouse recombinant FLAG-tagged PTGES expressed in baculovirus infected Hi-5 insect cells using prostaglandin H2 as substrate incubated f...More data for this Ligand-Target 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mouse recombinant FLAG-tagged PTGES expressed in baculovirus infected Hi-5 insect cells using prostaglandin H2 as substrate incubated f...More data for this Ligand-Target Pair Affinity DataIC50: 3.09E+3nMAssay Description:Inhibition of human recombinant FLAG-tagged PTGES expressed in baculovirus infected Hi-5 insect cells using prostaglandin H2 as substrate preincubate...More data for this Ligand-Target Pair

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Condition tags

endometriosis

MeSH descriptors

Carboxylic Acids Drug Discovery Drug Discovery Endometriosis Enzyme Inhibitors Prostaglandin-E Synthases Animals Animals Carboxylic Acids Carboxylic Acids Carboxylic Acids Carboxylic Acids Disease Models, Animal Disease Models, Animal Dose-Response Relationship, Drug Dose-Response Relationship, Drug Endometriosis Endometriosis Endometriosis Enzyme Inhibitors

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