A series of peri-substituted [4.3.0] bicyclic non-aromatic heterocycles have been identified as potent and selective hEP3 receptor antagonists. These molecules adopt a hair-pin conformation that overlaps with the endogenous ligand PGE2 and fits into an internally generated EP3 pharmacophore model. Optimized compounds show good metabolic stability and improved solubility over their corresponding bicyclic aromatic analogs.