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 cinnolines/quinolines was prepared and it was found that 4-phenyl-cinnoline/quinolines with either a 2',3' or 2',5'-disubstituted benzyloxy moiety or the 1-Me-7-indole methoxy moiety on the meta position of the 4-phenyl ring showed good binding selectivity for LXRbeta over LXRalpha. The LXRbeta binding selective modulators displayed good activity for inducing ABCA1 gene expression in J774 macrophage cell line and poor efficacy in the LXRalpha Gal4 functional assay. 26, 37 and 41 were examined for their ability to induce SREBP-1c gene expression in Huh-7 liver cell line and they were weak partial agonists.
Subject(s)
DNA-Binding Proteins/agonists , Heterocyclic Compounds, 2-Ring/chemistry , Quinolines/chemistry , Receptors, Cytoplasmic and Nuclear/agonists , ATP Binding Cassette Transporter 1 , ATP-Binding Cassette Transporters/metabolism , Animals , Cell Line , Computer Simulation , DNA-Binding Proteins/metabolism , Drug Discovery , Humans , Liver X Receptors , Mice , Orphan Nuclear Receptors , Quinolines/chemical synthesis , Quinolines/pharmacology , Receptors, Cytoplasmic and Nuclear/metabolism , Sterol Regulatory Element Binding Protein 1/metabolism , Structure-Activity RelationshipABSTRACT
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
The nuclear hormone receptor retinoic acid receptor-related orphan C2 (RORC2, also known as RORγt) is a promising target for the treatment of autoimmune diseases. A small molecule, inverse agonist of the receptor is anticipated to reduce production of IL-17, a key proinflammatory cytokine. Through a high-throughput screening approach, we identified a molecule displaying promising binding affinity for RORC2, inhibition of IL-17 production in Th17 cells, and selectivity against the related RORA and RORB receptor isoforms. Lead optimization to improve the potency and metabolic stability of this hit focused on two key design strategies, namely, iterative optimization driven by increasing lipophilic efficiency and structure-guided conformational restriction to achieve optimal ground state energetics and maximize receptor residence time. This approach successfully identified 3-cyano- N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1 H-pyrrolo[2,3- b]pyridin-5-yl)benzamide as a potent and selective RORC2 inverse agonist, demonstrating good metabolic stability, oral bioavailability, and the ability to reduce IL-17 levels and skin inflammation in a preclinical in vivo animal model upon oral administration.
Subject(s)
Drug Design , Drug Inverse Agonism , Nuclear Receptor Subfamily 1, Group F, Member 3/agonists , Pyridines/administration & dosage , Pyridines/pharmacology , Administration, Oral , Animals , Biological Availability , Drug Evaluation, Preclinical , Humans , Mice , Pyridines/pharmacokinetics , Th17 Cells/drug effects , Th17 Cells/metabolismABSTRACT
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
Much has been learned about the consequences of glucocorticoid receptor antagonism by studying steroidal active antagonists such as RU-38486 (1). In the liver glucocorticoid receptor antagonism suppresses hepatic glucose production decreasing plasma glucose levels; however, extrahepatic antagonism produces several undesirable side effects including activation of the hypothalamic pituitary adrenal axis. A series of nonsteroidal passive N-(3-dibenzylamino-2-alkyl-phenyl)-methanesulfonamide glucocorticoid receptor modulators was discovered. Liver selective and systemically available members of this series were found and characterized in diabetes and side effect rodent models. A highly liver selective member of this series, acid 14, shows efficacy in the ob/ob model of diabetes. It lowers plasma glucose, cholesterol, and free fatty acid concentrations and reduces the rate of body weight gain. The structurally related systemically available passive modulator 12 lowers glucose, HbA(1c), triglyceride, free fatty acid, and cholesterol levels. Interestingly, it did not acutely activate the hypothalamic pituitary adrenal axis in unstressed CD-1 mice or have the abortive effects observed with 1. These results indicate that passive GR antagonists may have utility as antidiabetic agents.
Subject(s)
Benzylamines/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Receptors, Glucocorticoid/antagonists & inhibitors , Sulfonamides/chemical synthesis , Alkaline Phosphatase/biosynthesis , Alkaline Phosphatase/genetics , Animals , Benzylamines/adverse effects , Benzylamines/pharmacology , Cells, Cultured , Cricetinae , Cricetulus , Dexamethasone/pharmacology , Female , Genes, Reporter , Glucocorticoids/pharmacology , Hepatocytes/drug effects , Hepatocytes/enzymology , Humans , Hypoglycemic Agents/adverse effects , Hypoglycemic Agents/pharmacology , Hypothalamo-Hypophyseal System/drug effects , Male , Mice , Pituitary-Adrenal System/drug effects , Pregnancy , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Glucocorticoid/genetics , Sulfonamides/adverse effects , Sulfonamides/pharmacology , Transcriptional Activation/drug effects , Tyrosine Transaminase/biosynthesis , Uterus/drug effectsABSTRACT
Hepatic blockade of glucocorticoid receptors (GR) suppresses glucose production and thus decreases circulating glucose levels, but systemic glucocorticoid antagonism can produce adrenal insufficiency and other undesirable side effects. These hepatic and systemic responses might be dissected, leading to liver-selective pharmacology, when a GR antagonist is linked to a bile acid in an appropriate manner. Bile acid conjugation can be accomplished with a minimal loss of binding affinity for GR. The resultant conjugates remain potent in cell-based functional assays. A novel in vivo assay has been developed to simultaneously evaluate both hepatic and systemic GR blockade; this assay has been used to optimize the nature and site of the linker functionality, as well as the choice of the GR antagonist and the bile acid. This optimization led to the identification of A-348441, which reduces glucose levels and improves lipid profiles in an animal model of diabetes.
Subject(s)
Bridged-Ring Compounds/chemical synthesis , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/chemical synthesis , Liver/metabolism , Receptors, Glucocorticoid/antagonists & inhibitors , Animals , Bile Acids and Salts/chemistry , Binding Sites , Bridged-Ring Compounds/chemistry , Bridged-Ring Compounds/pharmacology , CHO Cells , Cells, Cultured , Computer Simulation , Cricetinae , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Type 2/blood , Glucose/biosynthesis , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Hypothalamo-Hypophyseal System/drug effects , Hypothalamo-Hypophyseal System/physiology , Male , Mice , Models, Molecular , Pituitary-Adrenal System/drug effects , Pituitary-Adrenal System/physiology , Rats , Rats, Sprague-Dawley , Receptors, Glucocorticoid/metabolism , Structure-Activity RelationshipABSTRACT
Libraries of mifepristone analogs, MP-Acids, were designed and synthesized to increase the chances of identifying GR antagonists that possess liver-selective pharmacological profiles. MP-Acids were uniformly potent GR antagonists in binding and in cell-based functional assays. A high throughput pharmacokinetic selection strategy that employs the cassette dosing of MP-Acids was developed to identify liver-targeting compounds. Thus, resource-intensive in vivo assays to measure liver-selective pharmacology were enriched with GR antagonists that achieve high concentrations in the liver.
Subject(s)
Glucocorticoids/chemistry , Glucocorticoids/pharmacokinetics , Liver/metabolism , Mifepristone/analogs & derivatives , Receptors, Glucocorticoid/antagonists & inhibitors , Animals , Glucocorticoids/chemical synthesis , Rats , Rats, Inbred StrainsABSTRACT
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
A series of potent steroidal glucocorticoid receptor antagonists has been discovered. After conjugation to cholic acid, the compounds retained an affinity for GR in vitro and had modest in vivo efficacy.
Subject(s)
Bile Acids and Salts/chemistry , Receptors, Glucocorticoid/antagonists & inhibitors , Animals , Humans , Microsomes/drug effects , Microsomes/metabolism , Molecular Structure , Rats , Receptors, Glucocorticoid/metabolism , Structure-Activity RelationshipABSTRACT
Glucocorticoids amplify endogenous glucose production in type 2 diabetes by increasing hepatic glucose output. Systemic glucocorticoid blockade lowers glucose levels in type 2 diabetes, but with several adverse consequences. It has been proposed, but never demonstrated, that a liver-selective glucocorticoid receptor antagonist (LSGRA) would be sufficient to reduce hepatic glucose output (HGO) and restore glucose control to type 2 diabetic patients with minimal systemic side effects. A-348441 [(3b,5b,7a,12a)-7,12-dihydroxy-3-{2-[{4-[(11b,17b)-17-hydroxy-3-oxo-17-prop-1-ynylestra-4,9-dien-11-yl] phenyl}(methyl)amino]ethoxy}cholan-24-oic acid] represents the first LSGRA with significant antidiabetic activity. A-348441 antagonizes glucocorticoid-up-regulated hepatic genes, normalizes postprandial glucose in diabetic mice, and demonstrates synergistic effects on blood glucose in these animals when coadministered with an insulin sensitizer. In insulin-resistant Zucker fa/fa rats and fasted conscious normal dogs, A-348441 reduces HGO with no acute effect on peripheral glucose uptake. A-348441 has no effect on the hypothalamic pituitary adrenal axis or on other measured glucocorticoid-induced extrahepatic responses. Overall, A-348441 demonstrates that an LSGRA is sufficient to reduce elevated HGO and normalize blood glucose and may provide a new therapeutic approach for the treatment of type 2 diabetes.
Subject(s)
Blood Glucose/metabolism , Cholic Acids/pharmacology , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Estrone/analogs & derivatives , Glucose/metabolism , Liver/metabolism , Receptors, Glucocorticoid/antagonists & inhibitors , 3T3 Cells , Adipocytes/metabolism , Animals , Biotransformation/drug effects , Cell Differentiation/drug effects , Cholic Acids/metabolism , Diabetes Mellitus, Type 2/blood , Dogs , Drug Synergism , Estrone/metabolism , Estrone/pharmacology , Glucocorticoids/pharmacology , Glutamate-Ammonia Ligase/metabolism , Hypoglycemic Agents/pharmacology , Male , Mice , Obesity/metabolism , Prednisolone/pharmacology , Rats , Rats, Zucker , Reverse Transcriptase Polymerase Chain Reaction , Rosiglitazone , Thiazolidinediones/pharmacology , Tyrosine Transaminase/metabolismABSTRACT
A new class of selective nonsteroidal glucocorticoid receptor modulators typified by N-[3-[benzyl-(4-chloro-2-fluoro-benzyl)-amino]-2-methyl-phenyl]-methanesulfonamide 19 has been discovered.
Subject(s)
Receptors, Glucocorticoid/drug effects , Animals , Benzyl Compounds , Humans , Rats , Structure-Activity Relationship , SulfonamidesABSTRACT
Bile acid conjugates of a selective nonsteroidal glucocorticoid receptor modulator were prepared and evaluated. Potent GR binding conjugates that showed improved metabolic stability were discovered. However, cellular potency and pharmacokinetics were not substantially improved.
Subject(s)
Bile Acids and Salts/chemistry , Receptors, Glucocorticoid/drug effects , Animals , Bile Acids and Salts/pharmacokinetics , Biological Availability , Rats , Rats, Sprague-DawleyABSTRACT
A beta-C-glucuronide conjugate of the glucocorticoid receptor antagonist, Mifepristone 1, was prepared which maintained binding affinity, had modest in vitro activity, and was metabolically more stable than the parent. Pharmacokinetic studies suggest that the conjugate is recognized by the liver like O-glucuronides and may undergo a portion of the enterohepatic recirculation loop.