Identification of Selective ERRγ Inverse Agonists.

GSK5182 (4) is currently one of the lead compounds for the development of estrogen-related receptor gamma (ERR) inverse agonists. Here, we report the design, synthesis, pharmacological and in vitro absorption, distribution, metabolism, excretion, toxicity (ADMET) properties of a series of compounds related to 4. Starting from 4, a series of analogs were structurally modified and their ERR inverse agonist activity was measured. A key pharmacophore feature of this novel class of ligands is the introduction of a heterocyclic group for A-ring substitution in the core scaffold. Among the tested compounds, several of them are potent ERR inverse agonists as determined by binding and functional assays. The most promising compound, 15g, had excellent binding selectivity over related subtypes (IC50 = 0.44, >10, >10, and 10 M at the ERR, ERR, ERR, and ER subtypes, respectively). Compound 15g also resulted in 95% transcriptional repression at a concentration of 10 M, while still maintaining an acceptable in vitro ADMET profile. This novel class of ERR inverse agonists shows promise in the development of drugs targeting ERR-related diseases.