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, Nico Bräuer, Antonius ter Laak, Cornelia Preuße, Cornelia Preusse, Antje Rottmann, Dieter Heldmann, Ulrich Bothe, Thorsten Blume, Ludwig Zorn, Daryl Walter, Daryl S. Walter, Thomas M Zollner, Andreas Steinmeyer, 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 ⓘ

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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Condition tags

mesh:D004715endometriosischronic_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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