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1.
J Med Chem ; 53(8): 3412-6, 2010 Apr 22.
Article in English | MEDLINE | ID: mdl-20345102

ABSTRACT

Tertiary sulfonamides were identified in a HTS as dual liver X receptor (LXR, NR1H2, and NR1H3) ligands, and the binding affinity of the series was increased through iterative analogue synthesis. A ligand-bound cocrystal structure was determined which elucidated key interactions for high binding affinity. Further characterization of the tertiary sulfonamide series led to the identification of high affinity LXR antagonists. GSK2033 (17) is the first potent cell-active LXR antagonist described to date. 17 may be a useful chemical probe to explore the cell biology of this orphan nuclear receptor.


Subject(s)
Orphan Nuclear Receptors/antagonists & inhibitors , Sulfonamides/chemical synthesis , Animals , Cell Line , Crystallography, X-Ray , Haplorhini , Humans , Liver X Receptors , Models, Molecular , Orphan Nuclear Receptors/genetics , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , Transcriptional Activation/drug effects
2.
Mol Genet Metab ; 80(4): 398-407, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14654352

ABSTRACT

Adrenoleukodystrophy protein (ABCD1), a peroxisomal membrane protein, is mutated in patients affected by X-linked adrenoleukodystrophy (X-ALD). Adrenoleukodystrophy-related protein (ABCD2) is the closest relative of ABCD1. Pharmacological induction of ABCD2 gene expression has been proposed as a novel therapy strategy for X-ALD. Fibrates induce peroxisome proliferation and Abcd2 expression in rodent liver. Here we evaluate the possibility of using peroxisome proliferator-activated receptor alpha (PPARalpha) agonists for pharmacological induction of ABCD2 expression. In the liver of PPARalpha-deficient mice, both the constitutive and the fenofibrate-inducible Abcd2 gene expression was found to be PPARalpha-dependent. In the brain, PPARalpha-deficiency has no effect on Abcd2 expression. In mice orally treated with the novel, highly selective, and potent PPARalpha agonists GW 7647, GW 6867, and tetradecylthioacetic acid, Abcd2 expression was induced in liver and adrenal glands, but not in brain and testis. None of four putative PPREs identified in the 5(')-flanking DNA and in intron 1 of the Abcd2 gene conferred fibrate response in luciferase reporter assays. Thus, although fibrate-mediated Abcd2 induction is PPARalpha-dependent, it appears to be an indirect mechanism. Within the mouse Abcd2 promoter, a putative sterol regulatory element (SRE) similar in sequence and position to the characterized SRE sequence of the human ABCD2 promoter, was identified. A PPARalpha dependent induction of the sterol regulatory-binding protein 2 (SREBP2) and a down-regulation of SREBP1c mRNA levels could be demonstrated after fenofibrate treatment of mice. Our results suggest that the PPARalpha agonist-mediated induction of Abcd2 expression seems to be indirect and possibly mediated by SREBP2.


Subject(s)
Adrenoleukodystrophy/drug therapy , Receptors, Cytoplasmic and Nuclear/agonists , Transcription Factors/agonists , ATP Binding Cassette Transporter, Subfamily D , ATP-Binding Cassette Transporters/drug effects , ATP-Binding Cassette Transporters/genetics , Animals , Brain/drug effects , Brain/metabolism , Butyrates/pharmacology , CCAAT-Enhancer-Binding Proteins/drug effects , CCAAT-Enhancer-Binding Proteins/metabolism , DNA-Binding Proteins/drug effects , DNA-Binding Proteins/metabolism , Drug Evaluation, Preclinical/methods , Gene Expression Regulation/drug effects , Introns , Liver/drug effects , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Molecular Sequence Data , Phenylurea Compounds/pharmacology , Receptors, Cytoplasmic and Nuclear/deficiency , Response Elements/drug effects , Response Elements/genetics , Sterol Regulatory Element Binding Protein 1 , Sterol Regulatory Element Binding Protein 2 , Sterols/metabolism , Sulfides/pharmacology , Transcription Factors/deficiency , Transcription Factors/drug effects , Transcription Factors/metabolism
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