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1.
Bioorg Med Chem Lett ; 25(7): 1377-80, 2015 Apr 01.
Article in English | MEDLINE | ID: mdl-25752984

ABSTRACT

The design, synthesis, and structure activity relationships for a novel series of indoles as potent, selective, thyroid hormone receptor ß (TRß) agonists is described. Compounds with >50× binding selectivity for TRß over TRα were generated and evaluation of compound 1c from this series in a model of dyslipidemia demonstrated positive effects on plasma lipid endpoints in vivo.


Subject(s)
Acetates/pharmacology , Drug Design , Indoles/pharmacology , Thyroid Hormone Receptors beta/agonists , Acetates/chemical synthesis , Acetates/chemistry , Dose-Response Relationship, Drug , Humans , Indoles/chemical synthesis , Indoles/chemistry , Models, Molecular , Molecular Structure , Structure-Activity Relationship
2.
Proc Natl Acad Sci U S A ; 105(20): 7171-6, 2008 May 20.
Article in English | MEDLINE | ID: mdl-18474858

ABSTRACT

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.


Subject(s)
Biochemistry/methods , Selective Estrogen Receptor Modulators/pharmacology , Cell Line, Tumor , Cluster Analysis , Crystallography, X-Ray , Data Interpretation, Statistical , Humans , Ligands , Mass Spectrometry/methods , Models, Biological , Models, Molecular , Models, Statistical , Molecular Conformation , Protein Binding , Tissue Distribution
3.
J Med Chem ; 49(21): 6155-7, 2006 Oct 19.
Article in English | MEDLINE | ID: mdl-17034120

ABSTRACT

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.


Subject(s)
Estrogen Receptor beta/agonists , Flavonoids/chemical synthesis , Prostatic Hyperplasia/drug therapy , Selective Estrogen Receptor Modulators/chemical synthesis , Animals , Binding Sites , Crystallography, X-Ray , Estrogen Receptor alpha/chemistry , Estrogen Receptor beta/chemistry , Estrogens , Flavonoids/chemistry , Flavonoids/pharmacology , Humans , Ligands , Male , Mice , Models, Molecular , Molecular Structure , Prostate/drug effects , Prostate/pathology , Prostatic Hyperplasia/pathology , Selective Estrogen Receptor Modulators/chemistry , Selective Estrogen Receptor Modulators/pharmacology , Structure-Activity Relationship
4.
Mol Pharmacol ; 67(3): 948-54, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15602004

ABSTRACT

Guggulsterone (GS) is the active substance in guggulipid, an extract of the guggul tree, Commiphora mukul, used to treat a variety of disorders in humans, including dyslipidemia, obesity, and inflammation. The activity of GS has been suggested to be mediated by antagonism of the receptor for bile acids, the farnesoid X receptor (FXR). Here, we demonstrate that both stereoisomers of the plant sterol, (E)- and (Z)-GS, bind to the steroid receptors at a much higher affinity than to FXR. Both stereoisomers bind to the mineralocorticoid receptor (MR) with a Ki value of approximately 35 nM, which is greater than 100 times more potent than their affinity for FXR. Both (E)- and (Z)-GS also displayed high affinity for other steroid receptors, including the androgen (AR), glucocorticoid (GR), and progesterone receptors (PR) with Ki values ranging from 224 to 315 nM. In cell-based functional cotransfection assays, GSs behaved as antagonists of AR, GR, and MR, but as agonists of PR. Agonist activity was also demonstrated with estrogen receptor (ER) alpha; however, the potency was very low (EC50 > 5000 nM). In addition, GS displayed activity in functional assays in cell lines expressing endogenous AR, GR, ER, and PR. These data suggest that the variety of pharmacological effects exhibited by GS may be mediated by targeting several steroid receptors.


Subject(s)
Hypolipidemic Agents/pharmacology , Pregnenediones/pharmacology , Pregnenediones/pharmacokinetics , Receptors, Steroid/metabolism , Cell Line , Humans , Kinetics , Ligands , Phytotherapy , Plant Extracts/pharmacology , Radioligand Assay , Transfection
5.
Cancer Res ; 63(18): 6056-62, 2003 Sep 15.
Article in English | MEDLINE | ID: mdl-14522935

ABSTRACT

Trioxifene (LY133314) is a selective estrogen receptor modulator (SERM) with competitive binding activity against estradiol for estrogen receptor alpha (ERalpha) and antagonistic activity against ERalpha-mediated gene expression. The PAIII rat prostatic adenocarcinoma (PCa) is an androgen receptor-negative, ERalpha- and ERbeta-positive, spontaneously metastatic rodent tumor cell line. After s.c. implantation of 10(6) PAIII cells in the tail, s.c. administration of trioxifene (2.0, 4.0, 20.0, or 40.0 mg/kg-day) for 30 days produced significant (P < 0.05) inhibition of PAIII metastasis from the primary tumor in the tail to the gluteal and iliac lymph nodes (maximum nodal weight decreases, 86% and 88% from control values, respectively). PAIII metastasis to the lungs was significantly inhibited by trioxifene treatment. Numbers of pulmonary foci in PAIII-bearing rats were significantly (P < 0.05) reduced by trioxifene administration in a dose-related manner (maximal reduction, 98% from control values). Continual administration of the compound significantly (P < 0.05) extended survival of PAIII-bearing rats. Trioxifene inhibited the proliferation of PAIII cells at micromolar levels in vitro but did not slow growth of the primary tumor growth in the tail. Trioxifene administration also produced regression of male accessory sex organs. In PAIII-tumor-bearing animals, trioxifene administration produced a maximal regression of 76% for ventral prostate and 64% for seminal vesicle (P < 0.05 for both). SERMs may be preferable to estrogens given their efficacy in experimental PCa models and relative lack of side effects observed in clinical trials. Our data support the contention that trioxifene represents a SERM with potential antimetastatic efficacy for the treatment of androgen-independent, metastatic PCa.


Subject(s)
Adenocarcinoma/drug therapy , Prostatic Neoplasms/drug therapy , Pyrrolidines/pharmacology , Selective Estrogen Receptor Modulators/pharmacology , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Animals , Body Weight/drug effects , Cell Division/drug effects , Disease Models, Animal , Estrogen Receptor alpha , Estrogen Receptor beta , Genitalia, Male/drug effects , Luciferases/antagonists & inhibitors , Luciferases/metabolism , Lung Neoplasms/prevention & control , Lung Neoplasms/secondary , Lymphatic Metastasis , Male , Organ Size/drug effects , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Pyrrolidines/metabolism , Rats , Receptors, Androgen/biosynthesis , Receptors, Estrogen/biosynthesis , Receptors, Estrogen/metabolism , Selective Estrogen Receptor Modulators/metabolism , Testis/anatomy & histology , Testis/drug effects
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