ABSTRACT
A series of quinoline-3-carboxamide containing sulfones was prepared and found to have good binding affinity for LXRbeta and moderate binding selectivity over LXRalpha. The 8-Cl quinoline analog 33 with a high TPSA score, displayed 34-fold binding selectivity for LXRbeta over LXRalpha (LXRbeta IC(50)=16nM), good activity for inducing ABCA1 gene expression in a THP macrophage cell line, desired weak potency in the LXRalpha Gal4 functional assay, and low blood-brain barrier penetration in rat.
Subject(s)
Blood-Brain Barrier/metabolism , Orphan Nuclear Receptors/agonists , Quinolines/chemistry , Sulfones/chemistry , ATP Binding Cassette Transporter 1 , ATP-Binding Cassette Transporters/genetics , ATP-Binding Cassette Transporters/metabolism , Animals , Binding Sites , Cell Line , Computer Simulation , Humans , Hydrogen Bonding , Liver X Receptors , Orphan Nuclear Receptors/metabolism , Protein Binding , Quinolines/chemical synthesis , Quinolines/pharmacokinetics , Rats , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/pharmacokineticsABSTRACT
A series of 4-(3-biaryl)quinolines with sulfone substituents on the terminal aryl ring (8) was prepared as potential LXR agonists. High affinity LXRbeta ligands with generally modest binding selectivity over LXRalpha and excellent agonist potency in LXR functional assays were identified. Many compounds had LXRbeta binding IC(50) values <10 nM while the most potent had EC(50) values <1.0 nM in an ABCA1 mRNA induction assay in J774 mouse cells with efficacy comparable to T0901317. Sulfone 8a was further evaluated in LDL (-/-) mice and shown to reduce atherosclerotic lesion progression.
Subject(s)
Orphan Nuclear Receptors/agonists , Quinolines/chemistry , Sulfones/chemistry , Animals , Atherosclerosis/drug therapy , Binding Sites , Cell Line , Computer Simulation , Humans , Lipoproteins, LDL/deficiency , Lipoproteins, LDL/genetics , Lipoproteins, LDL/metabolism , Liver X Receptors , Mice , Mice, Knockout , Microsomes/metabolism , Orphan Nuclear Receptors/metabolism , Rats , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/therapeutic useABSTRACT
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
A series of 1-(3-aryloxyaryl)benzimidazoles incorporating a sulfone substituent (6) was prepared. High affinity LXR ligands were identified (LXRbeta binding IC(50) values <10nM), some with excellent agonist potency and efficacy in a functional assay of LXR activity measuring ABCA1 mRNA increases in human macrophage THP1 cells. The compounds were typically stable in liver microsome preparations and had good oral exposure in mice.
Subject(s)
Benzimidazoles/chemical synthesis , Orphan Nuclear Receptors/agonists , Sulfones/chemistry , ATP-Binding Cassette Transporters/genetics , ATP-Binding Cassette Transporters/metabolism , Animals , Benzimidazoles/chemistry , Benzimidazoles/pharmacokinetics , Cell Line , Humans , Liver X Receptors , Mice , Microsomes, Liver/metabolism , Orphan Nuclear Receptors/metabolism , RNA, Messenger/metabolism , Rats , Structure-Activity RelationshipABSTRACT
A series of 4-(3-aryloxyaryl)quinolines with sulfone substituents on the terminal aryl ring (7) was prepared as LXR agonists. High affinity LXR ligands with excellent agonist potency and efficacy in functional assays of LXR activity were identified. In general, these sulfone agonists were equal to or superior to previously described alcohol and amide analogs in terms of affinity, functional potency, and microsomal stability. Many of the sulfones had LXRbeta binding IC(50) values <10nM while the most potent compounds in an ABCA1 mRNA induction assay in J774 mouse cells had EC(50) values <10nM and were as efficacious as T0901317.
Subject(s)
Orphan Nuclear Receptors/agonists , Quinolines/chemistry , Sulfones/chemistry , ATP Binding Cassette Transporter 1 , ATP-Binding Cassette Transporters/genetics , ATP-Binding Cassette Transporters/metabolism , Animals , Binding Sites , Cell Line , Computer Simulation , Humans , Hydrocarbons, Fluorinated/chemistry , Hydrocarbons, Fluorinated/pharmacology , Hydrogen Bonding , Liver X Receptors , Mice , Microsomes, Liver/metabolism , Orphan Nuclear Receptors/metabolism , Quinolines/chemical synthesis , Quinolines/pharmacology , Rats , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , Sulfones/chemical synthesis , Sulfones/pharmacologyABSTRACT
A series of 4-(amido-biarylether)-quinolines was prepared as potential LXR agonists. Appropriate substitution with amide groups provided high affinity LXR ligands, some with excellent potency and efficacy in functional assays of LXR activity. Novel amide 4g had a binding IC(50)=1.9 nM for LXRbeta and EC(50)=34 nM (96% efficacy relative to T0901317) in an ABCA1 gene expression assay in mouse J774 cells, demonstrating that 4-(biarylether)-quinolines with appropriate amide substitution are potent LXR agonists.
Subject(s)
DNA-Binding Proteins/agonists , Quinolines/pharmacology , Receptors, Cytoplasmic and Nuclear/agonists , ATP Binding Cassette Transporter 1 , ATP-Binding Cassette Transporters/biosynthesis , ATP-Binding Cassette Transporters/genetics , Amides/chemical synthesis , Amides/chemistry , Amides/pharmacology , Animals , Cell Line , Crystallography, X-Ray , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/genetics , Gene Expression Regulation/drug effects , Kinetics , Ligands , Liver X Receptors , Mice , Models, Molecular , Orphan Nuclear Receptors , Quinolines/chemical synthesis , Quinolines/chemistry , Receptors, Cytoplasmic and Nuclear/chemistry , Receptors, Cytoplasmic and Nuclear/genetics , Transcriptional Activation/drug effects , TransfectionABSTRACT
A series of 4-(3-aryloxyaryl)quinolines with alcohol substituents on the terminal aryl ring was prepared as potential LXR agonists, in which an alcohol group replaced an amide in previously reported amide analogs. High affinity LXR ligands with excellent agonist potency and efficacy in a functional model of LXR activity were identified, demonstrating that alcohols can substitute for amides while retaining LXR activity. The most potent compound was 5b which had an IC(50)=3.3 nM for LXRbeta binding and EC(50)=12 nM (122% efficacy relative to T0901317) in an ABCA1 mRNA induction assay in J774 mouse cells.
Subject(s)
Alcohols/chemical synthesis , Models, Molecular , Orphan Nuclear Receptors/metabolism , Quinolines/chemical synthesis , Alcohols/chemistry , Alcohols/pharmacology , Animals , Binding, Competitive/physiology , Cell Line , Liver X Receptors , Macrophages , Magnetic Resonance Spectroscopy , Mass Spectrometry , Mice , Orphan Nuclear Receptors/agonists , Quinolines/chemistry , Quinolines/pharmacologyABSTRACT
A series of potent and binding selective LXRbeta agonists was developed using the previously reported non-selective LXR ligand WAY-254011 as a structural template. With the aid of molecular modeling, it was found that 2,3-diMe-Ph, 2,5-diMe-Ph, and naphthalene substituted quinoline acetic acids (such as quinoline 33, 37, and 38) showed selectivity for LXRbeta over LXRalpha in binding assays.
Subject(s)
Carboxylic Acids/chemistry , Carboxylic Acids/metabolism , DNA-Binding Proteins/agonists , Quinolines/chemistry , Quinolines/metabolism , Receptors, Cytoplasmic and Nuclear/agonists , Animals , Carboxylic Acids/pharmacology , Crystallography, X-Ray , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/metabolism , Gene Expression , Humans , Ligands , Liver X Receptors , Macrophages/drug effects , Macrophages/metabolism , Mice , Models, Molecular , Orphan Nuclear Receptors , Quinolines/pharmacology , Receptors, Cytoplasmic and Nuclear/chemistry , Receptors, Cytoplasmic and Nuclear/metabolism , Substrate Specificity , Transcriptional ActivationABSTRACT
PURPOSE: Physical activity (PA) is important for recovery after a breast cancer diagnosis; however, women's motivation to engage in PA can be impacted by disease and/or treatment, and can therefore be a challenge. This study explored factors associated with PA levels during chemotherapy among women with breast cancer. METHOD: The study had a cross-sectional descriptive and comparative design using a study-specific questionnaire. One hundred women with breast cancer receiving adjuvant chemotherapy were included. Data were analysed by Pearson's correlation coefficient and linear regression. The open question was subjected to manifest content analysis. RESULTS: Identified factors associated with engaging in PA during chemotherapy treatment were: being physically active before diagnosis, and the information given by the oncology nurse before the treatment start. The physically active women experienced higher psychological wellbeing, less fatigue, and faster recovery after treatment. They also experienced an overall feeling of fitness. CONCLUSION: It seems that PA is associated with less fatigue, better recovery between chemotherapy treatments, and a better mental condition leading to wellbeing. Information given by the oncology nurse may be an important factor for being physically active. Women with breast cancer need to get specific advice about and support in engaging in PA to feel better during chemotherapy treatment. Further research is required to develop guidelines for advice about and support regarding PA during chemotherapy treatment.
Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/psychology , Exercise/psychology , Motivation , Adult , Chemotherapy, Adjuvant , Cross-Sectional Studies , Female , Humans , Middle Aged , Surveys and QuestionnairesABSTRACT
A structure-based approach was used to optimize our new class of quinoline LXR modulators leading to phenyl acetic acid substituted quinolines 15 and 16. Both compounds displayed good binding affinity for LXRbeta and LXRalpha and were potent activators in LBD transactivation assays. The compounds also increased expression of ABCA1 and stimulated cholesterol efflux in THP-1 cells. Quinoline 16 showed good oral bioavailability and in vivo efficacy in a LDLr knockout mouse model for lesions.
Subject(s)
Anticholesteremic Agents/chemical synthesis , Atherosclerosis/drug therapy , DNA-Binding Proteins/agonists , Phenylacetates/chemical synthesis , Quinolines/chemical synthesis , Receptors, Cytoplasmic and Nuclear/agonists , ATP Binding Cassette Transporter 1 , ATP-Binding Cassette Transporters/biosynthesis , Animals , Anticholesteremic Agents/chemistry , Anticholesteremic Agents/pharmacology , Binding Sites , Biological Availability , Cell Line , Cholesterol/metabolism , DNA-Binding Proteins/genetics , Drug Stability , Female , Humans , In Vitro Techniques , Ligands , Liver X Receptors , Male , Mice , Mice, Inbred C57BL , Microsomes, Liver/metabolism , Models, Molecular , Molecular Structure , Orphan Nuclear Receptors , Phenylacetates/chemistry , Phenylacetates/pharmacology , Protein Structure, Tertiary , Quinolines/chemistry , Quinolines/pharmacology , Receptors, Cytoplasmic and Nuclear/genetics , Structure-Activity Relationship , Transcriptional ActivationABSTRACT
A series of phenyl sulfone substituted quinoxaline were prepared and the lead compound 13 (WYE-672) was shown to be a tissue selective LXR Agonist. Compound 13 demonstrated partial agonism for LXRbeta in kidney HEK-293 cells but did not activate Gal4 LXRbeta fusion proteins in huh-7 liver cells. Although 13 showed potent binding affinity to LXRbeta (IC(50) = 53 nM), it had little binding affinity for LXRalpha (IC(50) > 1.0 microM) and did not recruit any coactivator/corepressor peptides in the LXRalpha multiplex assay. However, compound 13 showed good agonism in THP-1 cells with respect to increasing ABCA1 gene expression and good potency on cholesterol efflux in THP-1 foam cells. In an eight-week lesion study in LDLR -/- mice, compound 13 showed reduction of aortic arch lesion progression and no plasma or hepatic triglyceride increase. These results suggest quinoxaline 13 may have an improved biological profile for potential use as a therapeutic agent.
Subject(s)
Orphan Nuclear Receptors/agonists , Quinoxalines/chemical synthesis , Sulfones/chemical synthesis , ATP Binding Cassette Transporter 1 , ATP-Binding Cassette Transporters/biosynthesis , Animals , Area Under Curve , Atherosclerosis/drug therapy , Atherosclerosis/metabolism , Cell Line , Cholesterol/metabolism , Duodenum/metabolism , Half-Life , Humans , Kidney/metabolism , Liver/metabolism , Liver X Receptors , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Models, Molecular , Organ Specificity , Orphan Nuclear Receptors/genetics , Quinoxalines/chemistry , Quinoxalines/pharmacology , Radioligand Assay , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacology , Transcriptional Activation , Triglycerides/metabolismABSTRACT
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
A series of phenyl acetic acid based quinolines was prepared as LXR modulators. An SAR study in which the C-3 and C-8 positions of the quinoline core were varied led to the identification of two potent LXR agonists 23 and 27. Both compounds displayed good binding affinity for LXRbeta and LXRalpha, and increased expression of ABCA1 in THP-1 cells. These two compounds also had desirable pharmacokinetic profiles in mice and displayed in vivo efficacy in a 12-week Apo E knockout mouse lesion model.
Subject(s)
Atherosclerosis/prevention & control , DNA-Binding Proteins/agonists , Phenylacetates/chemical synthesis , Phenylacetates/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , Receptors, Cytoplasmic and Nuclear/agonists , Animals , Apolipoproteins E/genetics , Atherosclerosis/genetics , Atherosclerosis/pathology , CHO Cells , Carboxylic Acids/chemical synthesis , Carboxylic Acids/pharmacology , Chromatography, High Pressure Liquid , Cricetinae , Cricetulus , DNA-Binding Proteins/genetics , Humans , Indicators and Reagents , Liver X Receptors , Magnetic Resonance Spectroscopy , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Orphan Nuclear Receptors , Receptors, Cytoplasmic and Nuclear/genetics , Recombinant Proteins/metabolism , Solvents , Spectrometry, Mass, Electrospray Ionization , Structure-Activity Relationship , Transcriptional Activation/geneticsABSTRACT
The structures of the liver X receptor LXRbeta (NR1H2) have been determined in complexes with two synthetic ligands, T0901317 and GW3965, to 2.1 and 2.4 A, respectively. Together with its isoform LXRalpha (NR1H3) it regulates target genes involved in metabolism and transport of cholesterol and fatty acids. The two LXRbeta structures reveal a flexible ligand-binding pocket that can adjust to accommodate fundamentally different ligands. The ligand-binding pocket is hydrophobic but with polar or charged residues at the two ends of the cavity. T0901317 takes advantage of this by binding to His-435 close to H12 while GW3965 orients itself with its charged group in the opposite direction. Both ligands induce a fixed "agonist conformation" of helix H12 (also called the AF-2 domain), resulting in a transcriptionally active receptor.