Identification\nof a Benzimidazolecarboxylic Acid Derivative\n(BAY 1316957) as a Potent and Selective Human Prostaglandin\nE2 Receptor Subtype 4 (hEP4-R) Antagonist for the Treatment of Endometriosis

The\npresence and growth of endometrial tissue outside the uterine\ncavity in endometriosis patients are primarily driven by hormone-dependent\nand inflammatory processesthe latter being frequently associated\nwith severe, acute, and chronic pelvic pain. The EP4 subtype of prostaglandin\nE2 (PGE2) receptors (EP4-R) is a particularly promising anti-inflammatory\nand antinociceptive target as both this receptor subtype and the pathways\nforming PGE2 are highly expressed in endometriotic lesions. High-throughput\nscreening resulted in the identification of benzimidazole derivatives\nas novel hEP4-R antagonists. Careful structure–activity relationship\ninvestigation guided by rational design identified a methyl substitution\nadjacent to the carboxylic acid as an appropriate means to accomplish\nfavorable pharmacokinetic properties by reduction of glucuronidation.\nFurther optimization led to the identification of benzimidazolecarboxylic\nacid BAY 1316957, a highly potent, specific, and selective\nhEP4-R antagonist with excellent drug metabolism and pharmacokinetics\nproperties. Notably, treatment with BAY 1316957 can be\nexpected to lead to prominent and rapid pain relief and significant\nimprovement of the patient’s quality of life.