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1.
Bioorg Med Chem Lett ; 21(22): 6842-51, 2011 Nov 15.
Article in English | MEDLINE | ID: mdl-21963986

ABSTRACT

We report a SAR of non-steroidal glucocorticoid mimetics that utilize indoles as A-ring mimetics. Detailed SAR is discussed with a focus on improving PR and MR selectivity, GR agonism, and in vitro dissociation profile. SAR analysis led to compound (R)-33 which showed high PR and MR selectivity, potent agonist activity, and reduced transactivation activity in the MMTV and aromatase assays. The compound is equipotent to prednisolone in the LPS-TNF model of inflammation. In mouse CIA, at 30 mg/kg compound (R)-33 inhibited disease progression with an efficacy similar to the 3 mg/kg dose of prednisolone.


Subject(s)
Glucocorticoids/chemistry , Glucocorticoids/pharmacology , Indoles/chemistry , Indoles/pharmacology , Receptors, Glucocorticoid/agonists , Receptors, Glucocorticoid/metabolism , Animals , HeLa Cells , Humans , Mice , Models, Molecular , Structure-Activity Relationship
2.
Bioorg Med Chem Lett ; 17(18): 5091-5, 2007 Sep 15.
Article in English | MEDLINE | ID: mdl-17681466

ABSTRACT

We have recently reported the discovery of a novel class of glucocorticoid receptor (GR) antagonists, exemplified by 3, containing a 1,2-dihydroquinoline molecular scaffold. Further SAR studies of these antagonists uncovered chemical modifications conveying agonist functional activity to this series. These agonists exhibit good GR binding affinity and are selective against other nuclear hormone receptors.


Subject(s)
Quinolines/chemistry , Quinolines/pharmacology , Receptors, Glucocorticoid/agonists , Quinolines/metabolism , Receptors, Glucocorticoid/metabolism , Structure-Activity Relationship
3.
Bioorg Med Chem Lett ; 16(6): 1549-52, 2006 Mar 15.
Article in English | MEDLINE | ID: mdl-16386422
4.
Biochemistry ; 43(40): 12750-60, 2004 Oct 12.
Article in English | MEDLINE | ID: mdl-15461447

ABSTRACT

Major histocompatibility complex (MHC) class II genes are regulated at the transcriptional level by coordinate action of a limited number of transcription factors that include regulatory factor X (RFX), class II transcriptional activator (CIITA), nuclear factor Y (NF-Y), and cyclic AMP-response element binding protein (CREB). Here, the MHC class-II-specific transcription factors and CREB were expressed in insect cells with recombinant baculoviruses, isolated, and characterized by biochemical and biophysical methods. Analytical ultracentrifugation (AUC) has demonstrated that RFX is a heterotrimer. A heterodimer of RFX5 and RFX-AP was also observed. A high-affinity interaction (K(d) = 25 nM) between RFX5 and RFX-AP was measured by isothermal titration calorimetry (ITC), while the interaction between RFX-AP and RFX-ANK is at least an order of magnitude weaker. The biophysical data show that the interaction between RFX-AP and RFX5 is a key event in the assembly of the heterotrimer. Fluorescence anisotropy was used to determine protein-nucleic acid binding affinities for the RFX subunits and complexes binding to duplex DNA. The RFX5 subunit was found to drive recognition of the promoter, while the auxiliary RFX-AP and RFX-ANK subunits were shown to contribute to the specificity of binding for the overall complex. AUC experiments demonstrate that in the absence of additional subunits, monomeric RFX5 binds to X-box DNA with a 1:1 stoichiometry. Interactions between CREB, CIITA, and RFX in the absence of DNA were demonstrated using bead-based immunoprecipitation assays, confirming that preassociation with DNA is not required for forming the macromolecular assemblies that drive MHC class II gene expression.


Subject(s)
DNA-Binding Proteins/chemistry , DNA-Binding Proteins/metabolism , Histocompatibility Antigens Class II/genetics , Promoter Regions, Genetic/genetics , Transcription Factors/chemistry , Transcription Factors/metabolism , Animals , Cell Line , Cyclic AMP Response Element-Binding Protein/metabolism , DNA/genetics , DNA/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/isolation & purification , Gene Expression Regulation , Macromolecular Substances , Nuclear Proteins/metabolism , Protein Structure, Quaternary , Regulatory Factor X Transcription Factors , Spodoptera , Substrate Specificity , Trans-Activators/metabolism , Transcription Factors/genetics , Transcription Factors/isolation & purification
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