Synthesis and biological evaluation of novel 4-hydroxytamoxifen analogs as estrogen-related receptor gamma inverse agonists

Estrogen-related receptor gamma (ERR gamma) has recently been recognized as an attractive target for treating inflammation, cancer, and metabolic disorders. Herein, we discovered and demonstrated the in vitro pharmacology as well as the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of chemical entities that could act as highly selective inverse agonists for ERR gamma. The results were comparable to those for GSK5182 (4), a leading ERR gamma inverse agonist ligand. Briefly, the half maximal inhibitory concentration (IC50) range of the synthesized compounds for ERR gamma was 0.1-10 mu M. Impressively, compound 24e exhibited potency comparable to 4 but was more selective for ERR gamma over three other subtypes: ERR alpha, ERR beta, and estrogen receptor alpha. Furthermore, compound 24e exhibited a superior in vitro ADMET profile compared to the other compounds. Thus, the newly synthesized class of ERR gamma inverse agonists could be lead candidates for developing clinical therapies for ERR gamma-related disorders. (C) 2016 Elsevier Masson SAS. All rights reserved.