OSU-ERβ-12: a promising pre-clinical candidate selective estrogen receptor beta agonist

Estrogen receptor beta (ERβ) is a favorable therapeutic target for mediating inflammation, attenuating fibrosis, and treating cancer. However, selectively targeting ERβ over estrogen receptor alpha (ERα) has been a longstanding challenge. Recently, we developed OSU-ERβ-12, a novel carborane-based ERβ agonist that has a greater than 100-fold selectivity for ERβ over ERα. In this study, we compare the pharmacokinetics and functional activity of OSU-ERβ-12 against the clinical comparator ERβ agonist erteberel (LY500307) in multiple model systems. Pharmacokinetic profiling revealed OSU-ERβ-12 to have superior pharmacokinetics in pre-clinical models compared to LY500307 while maintaining a similar ERβ selectivity. Additionally, OSU-ERβ-12 displayed high human liver microsome stability and negligible CYP, hERG, and off-target interactions. Overall, OSU-ERβ-12 is a potent, selective, pharmacokinetically superior ERβ agonist that warrants additional study.