Discovery of 1‐(Cyclopropylmethyl)‐2‐(Dibenzo[b,d]Thiophen‐2‐yl)‐<scp>1H</scp>‐Benzo[d]Imidazole‐5‐Carboxylic Acid as Orally Bioavailable <scp>EP4</scp> Receptor Antagonist

The prostaglandin E₂ (PGE₂) regulates several biological processes via interaction with 1 of 4 E-type prostanoid receptors (EP1-EP4). The E-type prostanoid receptor 4 (EP4) is expressed primarily on myeloid cells, T lymphocytes, and tumor cells, and has emerged as a major contributor to PGE₂-mediated enhancement of tumor survival pathways and as a suppressor of innate and adaptive antitumor immune responses. To date, significant work on the discovery of EP4 receptor antagonists has been carried out, but no compound has been approved for use in humans yet. Toward our aim of discovering potential EP4 antagonists, a pharmacophore-based scaffold-hopping approach combined with docking studies has been envisaged. As a result, compound 4 was found to be a non-toxic, potent EP4 antagonist binding in the orthosteric site. This compound exhibited good aqueous solubility, with acceptable in vitro metabolic stability and permeability. Albeit high protein binding, it displayed sustained exposure and significant oral bioavailability in mice and can thus have the potential for further optimization to yield next-generation EP4 antagonists.