Identification of a Benzimidazolecarboxylic Acid Derivative (BAY 1316957) as a Potent and Selective Human Prostaglandin E2 Receptor Subtype 4 (hEP4-R) Antagonist for the Treatment of Endometriosis

Stefan Bäurle, Jens Nagel, Olaf Peters, Peters O, Bräuer N, Nico Bräuer, Antonius ter Laak, Preusse C, Cornelia Preusse, Cornelia Preuße, Antje Rottmann, Rottmann A, Dieter Heldmann, Heldmann D, Ulrich Bothe, Bothe U, Thorsten Blume, Blume T, Ludwig Zorn, Zorn L, Daryl S. Walter, Daryl Walter, Walter D, Thomas M Zollner, Zollner TM, Andreas Steinmeyer, Steinmeyer A, Langer G, Gernot Langer
Journal of medicinal chemistry · 2019 · vol. 62(5) , pp. 2541–2563 · doi:10.1021/acs.jmedchem.8b01862 · PMID:30707023 · W2911674382
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⚙ AI-generated summary by claude@2026-06, 2026-06-06 ⓘ

Researchers identified the benzimidazolecarboxylic acid derivative BAY 1316957 as a potent and selective hEP4-R antagonist with favorable drug metabolism and pharmacokinetic properties for endometriosis treatment.

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

The paper reports the identification of a benzimidazolecarboxylic acid derivative, BAY 1316957, as a potent and selective antagonist of the human prostaglandin E2 receptor subtype 4 (hEP4-R). Antagonist activity was assessed in a human EP4R assay by measuring inhibition of agonist-induced cAMP production using a fluorescent cAMP tracer (cAMP-d2) based FRET approach, with reported IC50 values ranging from single-digit to low hundreds of nM. The text provided is limited to affinity/IC50-type assay readouts and does not include additional details such as full experimental methods, selectivity profiling across other receptors, or explicit limitations beyond the available dataset. Relevance to endometriosis: the title explicitly frames BAY 1316957 as a treatment candidate for endometriosis via EP4R antagonism, while the paper’s provided content focuses on receptor functional antagonism rather than clinical or tissue efficacy data.

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Abstract

The presence and growth of endometrial tissue outside the uterine cavity in endometriosis patients are primarily driven by hormone-dependent and inflammatory processes-the latter being frequently associated with severe, acute, and chronic pelvic pain. The EP4 subtype of prostaglandin E2 (PGE2) receptors (EP4-R) is a particularly promising anti-inflammatory and antinociceptive target as both this receptor subtype and the pathways forming PGE2 are highly expressed in endometriotic lesions. High-throughput screening resulted in the identification of benzimidazole derivatives as novel hEP4-R antagonists. Careful structure-activity relationship investigation guided by rational design identified a methyl substitution adjacent to the carboxylic acid as an appropriate means to accomplish favorable pharmacokinetic properties by reduction of glucuronidation. Further optimization led to the identification of benzimidazolecarboxylic acid BAY 1316957, a highly potent, specific, and selective hEP4-R antagonist with excellent drug metabolism and pharmacokinetics properties. Notably, treatment with BAY 1316957 can be expected to lead to prominent and rapid pain relief and significant improvement of the patient's quality of life.
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Report error Found 41 Enz. 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activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 6.10nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 6.80nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 7nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 13nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 15nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 15nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 16nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 17nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 18nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 22nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 24nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 25nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 34nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 34nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 35nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 44nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 52nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 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production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 113nMAssay Description:Antagonist activity at mouse EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 134nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 148nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 158nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 166nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 222nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 257nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 286nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 366nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 612nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 733nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 751nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 1.42E+3nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair Affinity DataIC50: 3.12E+3nMAssay Description:Antagonist activity at human EP4R assessed as inhibition of agonist-induced cAMP production by fluorescent cAMP tracer cAMP-d2 based FRET assayMore data for this Ligand-Target Pair

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Condition tags

endometriosischronic_pelvic_pain

MeSH descriptors

Benzimidazoles Benzimidazoles Endometriosis Receptors, Prostaglandin E, EP4 Subtype Benzimidazoles Benzimidazoles Endometriosis Female High-Throughput Screening Assays Humans Receptors, Prostaglandin E, EP4 Subtype Structure-Activity Relationship

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