Characterization of a new class of selective nonsteroidal progesterone receptor agonists.

摘要: Abstract The identification of a new series selective nonsteroidal progesterone receptor (PR) agonists is reported. Using high-throughput screening assay based on the measurement transactivation mouse mammary tumor virus promoter-driven luciferase reporter (MMTV-Luc) in human breast cancer T47D cells, benzimidazole-2-thione analog was identified. Compound 1 showed an apparent EC50 53 nM and efficacy 93% with respect to progesterone. It binds PR high affinity (Ki=89 nM), but had no or very low for other steroid hormone receptors. Structure–activity relationship studies analogs revealed critical positions binding potency as well selectivity, exemplified by 25. 25 (Ki=28 nM) at least >1000-fold selectivity versus Molecular modeling suggested that these overlap favorably ligand-binding domain PR. In compound acted full agonist MMTV-Luc assay, induction endogenous alkaline phosphatase activity values 4 9 nM, respectively. immature rat model, provided significant suppression estrogen-induced endometrium hypertrophy measured luminal epithelial height. contrast, inactive luteinizing release young ovariectomized rats. These constitute excellent profile. differential activities observed vivo progestogenic assays models suggest can act modulators.