Novel 3-aryl indoles as progesterone receptor antagonists for uterine fibroids.

We report the synthesis and characterization of novel 3-aryl indoles as potent and efficacious progesterone receptor (PR) antagonists with potential for the treatment of uterine fibroids. These compounds demonstrated excellent selectivity over other steroid nuclear hormone receptors such as the mineralocorticoid receptor (MR). They were prepared from 2-bromo-6-nitro indole in four to six steps using a Suzuki cross-coupling as the key step. Compound 8f was orally active in the complement 3 model of progesterone antagonism in the rat uterus and demonstrated partial antagonism in the McPhail model of progesterone activity.

Unique ligand binding patterns between estrogen receptor alpha and beta revealed by hydrogen-deuterium exchange.

Here we present the use of hydrogen-deuterium exchange (HDX) mass spectrometry in analyzing the estrogen receptor beta ligand binding domain (ERbeta LBD) in the absence and presence of a variety of chemical compounds with different binding modes and pharmacological properties. Previously, we reported the use of HDX as a method for predicting the tissue selectivity of ERalpha ligands. HDX profiles of ERalpha LBD in complex with ligand could differentiate compounds of the same chemotype. In contrast, similar analysis of ERbeta LBD showed correlation to the compound chemical structures but little correlation with compound tissue selectivity. The different HDX patterns observed for ERbeta LBD when compared to those for ERalpha LBD bound to the same chemical compounds serve as an indication that ERbeta LBD undergoes a different structural response to the same ligand when compared to ERalpha LBD. The conformational dynamics revealed by HDX for ERbeta LBD together with those for ERalpha LBD shed light on ER ligand interactions and offer new structural insights. The compound-specific perturbations in HDX kinetics observed for each of the two isoforms should aid the development of subtype-selective ER ligands.

Prediction of the tissue-specificity of selective estrogen receptor modulators by using a single biochemical method.

Here, we demonstrate that a single biochemical assay is able to predict the tissue-selective pharmacology of an array of selective estrogen receptor modulators (SERMs). We describe an approach to classify estrogen receptor (ER) modulators based on dynamics of the receptor-ligand complex as probed with hydrogen/deuterium exchange (HDX) mass spectrometry. Differential HDX mapping coupled with cluster and discriminate analysis effectively predicted tissue-selective function in most, but not all, cases tested. We demonstrate that analysis of dynamics of the receptor-ligand complex facilitates binning of ER modulators into distinct groups based on structural dynamics. Importantly, we were able to differentiate small structural changes within ER ligands of the same chemotype. In addition, HDX revealed differentially stabilized regions within the ligand-binding pocket that may contribute to the different pharmacology phenotypes of the compounds independent of helix 12 positioning. In summary, HDX provides a sensitive and rapid approach to classify modulators of the estrogen receptor that correlates with their pharmacological profile.

Benzopyrans are selective estrogen receptor beta agonists with novel activity in models of benign prostatic hyperplasia.

Benzopyran selective estrogen receptor beta agonist-1 (SERBA-1) shows potent, selective binding and agonist function in estrogen receptor beta (ERbeta) in vitro assays. X-ray crystal structures of SERBA-1 in ERalpha and beta help explain observed beta-selectivity of this ligand. SERBA-1 in vivo demonstrates involution of the ventral prostate in CD-1 mice (ERbeta effect), while having no effect on gonadal hormone levels (ERalpha effect) at 10x the efficacious dose, consistent with in vitro properties of this molecule.