ABSTRACT
Replacement of a quinoline with an imidazo[1,2-a]pyridine in a series of liver X receptor (LXR) agonists incorporating a [3-(sulfonyl)aryloxyphenyl] side chain provided high affinity LXR ligands 7. In functional assays of LXR activity, good agonist potency and efficacy were found for several analogs.
Subject(s)
Orphan Nuclear Receptors/agonists , Pyridines/chemical synthesis , Quinolines/chemical synthesis , Sulfones/chemical synthesis , ATP-Binding Cassette Transporters/genetics , ATP-Binding Cassette Transporters/metabolism , Animals , Hep G2 Cells , Humans , Liver X Receptors , Mice , Microsomes, Liver/metabolism , Orphan Nuclear Receptors/metabolism , Protein Binding , Pyridines/chemistry , Pyridines/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , RNA, Messenger/metabolism , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacologyABSTRACT
The discovery of novel intervention points in the inflammatory pathway has been a focus of drug development in recent years. We have identified pathway selective ligands for the estrogen receptor (ER) that inhibit NF-kappaB mediated inflammatory gene expression causing a reduction of cytokines, chemokines, adhesion molecules and inflammatory enzymes. SAR development of a series of 4-(Indazol-3-yl)-phenols has led to the identification of WAY-169916 an orally active non-steroidal ligand with the potential use in the treatment of inflammatory diseases without the classical proliferative effects associated with non-selective estrogens.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Inflammation/drug therapy , Inflammation/immunology , Pyrazoles/therapeutic use , Receptors, Estrogen/antagonists & inhibitors , Receptors, Estrogen/immunology , Chronic Disease , Humans , Ligands , Molecular Structure , Structure-Activity RelationshipABSTRACT
Pathway-selective ligands for the estrogen receptor (ER) inhibit NF-kappaB-mediated inflammatory gene expression causing a reduction of cytokines, chemokines, adhesion molecules, and inflammatory enzymes. SAR development of a series of 4-(indazol-3-yl)phenols has led to the identification of WAY-169916 an orally active nonsteroidal ligand with the potential use in the treatment of rheumatoid arthritis without the classical proliferative effects associated with estrogens.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Arthritis, Rheumatoid/drug therapy , Indazoles/chemical synthesis , Phenols/chemical synthesis , Receptors, Estrogen/drug effects , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Arthritis, Experimental/drug therapy , Arthritis, Experimental/pathology , Cell Line , Estrogen Receptor alpha/chemistry , Estrogen Receptor alpha/drug effects , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/chemistry , Estrogen Receptor beta/drug effects , Estrogen Receptor beta/metabolism , Humans , Indazoles/chemistry , Indazoles/pharmacology , Ligands , Mice , Mice, Inbred C57BL , Models, Molecular , NF-kappa B/biosynthesis , NF-kappa B/genetics , Phenols/chemistry , Phenols/pharmacology , Rats , Rats, Inbred Lew , Receptors, Estrogen/chemistry , Receptors, Estrogen/metabolism , Structure-Activity RelationshipABSTRACT
A series of substituted 2-benzyl-3-aryl-7-trifluoromethylindazoles were prepared as LXR modulators. These compounds were partial agonists in transactivation assays when compared to 1 (T0901317) and were slightly weaker with respect to potency and efficacy on LXRalpha than on LXRbeta. Lead compounds in this series 12 (WAY-252623) and 13 (WAY-214950) showed less lipid accumulation in HepG2 cells than potent full agonists 1 and 3 (WAY-254011) but were comparable in efficacy to 1 and 3 with respect to cholesterol efflux in THP-1 foam cells, albeit weaker in potency. Compound 13 reduced aortic lesion area in LDLR knockout mice equivalently to 3 or positive control 2 (GW3965). In a 7-day hamster model, compound 13 showed a lesser propensity for plasma TG elevation than 3, when the compounds were compared at doses in which they elevated ABCA1 and ABCG1 gene expression in duodenum and liver at equal levels. In contrast to results previously published for 2, the lack of TG effect of 13 correlated with its inability to increase liver fatty acid synthase (FAS) gene expression, which was up-regulated 4-fold by 3. These results suggest indazoles such as 13 may have an improved profile for potential use as a therapeutic agent.
Subject(s)
Arteriosclerosis/drug therapy , DNA-Binding Proteins/agonists , Indazoles/pharmacology , Liver/metabolism , Receptors, Cytoplasmic and Nuclear/agonists , Triglycerides/biosynthesis , Animals , Arteriosclerosis/metabolism , Cell Differentiation/drug effects , Cell Line , Cricetinae , Crystallography, X-Ray , DNA-Binding Proteins/metabolism , Humans , Hydrogen Bonding , Indazoles/chemical synthesis , Indazoles/chemistry , Ligands , Liver/drug effects , Liver X Receptors , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Models, Animal , Models, Molecular , Molecular Structure , Orphan Nuclear Receptors , Receptors, Cytoplasmic and Nuclear/metabolism , Recombinant Proteins/drug effects , Recombinant Proteins/metabolism , Structure-Activity Relationship , Triglycerides/bloodABSTRACT
Inflammation is now recognized as a key component in a number of diseases such as atherosclerosis, rheumatoid arthritis, and inflammatory bowel disease. The transcription factor NF-kappaB has been shown to be involved in both the early and late stages of the inflammatory-proliferative process. In this report, we describe the identification of the pathway-selective estrogen receptor (ER) ligand, WAY-169916, that inhibits NF-kappaB transcriptional activity but is devoid of conventional estrogenic activity. This pathway-selective ligand does not promote the classic actions of estrogens such as stimulation of uterine proliferation or ER-mediated gene expression, but is a potent antiinflammatory agent, as demonstrated in the HLA-B27 transgenic rat model of inflammatory bowel disease. Our results indicate the potential utility of pathway-selective ER ligands such as WAY-169916 in the treatment of chronic inflammatory diseases.
Subject(s)
NF-kappa B/antagonists & inhibitors , Pyrazoles/metabolism , Pyrazoles/pharmacology , Receptors, Estrogen/metabolism , Transcription, Genetic/drug effects , Animals , Animals, Genetically Modified , Cell Line , Estrogen Receptor alpha/genetics , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/genetics , Estrogen Receptor beta/metabolism , Female , HLA-B27 Antigen/genetics , Humans , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/genetics , Inflammatory Bowel Diseases/metabolism , Ligands , Male , Mice , Mice, Inbred C57BL , Pyrazoles/chemistry , Rats , Uterus/drug effects , Uterus/metabolismABSTRACT
The synthesis and SAR of a series of human beta3 adrenoreceptor agonists based on a template derived from a common pharmacophore coupled with 4-aminomethylpiperidine is described. Potent and selective agents were identified such as 26 that was in vitro active in CHO cells expressing human beta3-AR (EC50=49 nM, IA=1.1), and in vivo active in a transgenic mouse model.
Subject(s)
Adrenergic beta-3 Receptor Agonists , Adrenergic beta-Agonists/chemical synthesis , Adrenergic beta-Agonists/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Animals , CHO Cells , Cricetinae , Humans , Indicators and Reagents , Mice , Mice, Transgenic , Receptors, Adrenergic, beta-3/genetics , Structure-Activity RelationshipABSTRACT
The synthesis and SAR of a series of beta3 adrenoreceptor agonists based on a novel template derived from 4-aminomethylpiperidine coupled with a common pharmacophore, arylethylamine, is described. This combination led to the identification of human beta3 adrenoreceptor agonists with in vivo activity in a transgenic mouse model.