ABSTRACT
As part of our efforts to develop agents for CNS diseases, we have been focused on the 5-HT(6) receptor in order to identify potent and selective ligands for cognitive enhancement. Herein we report the identification of a novel series of 5-piperazinyl-3-sulfonylindazoles as potent and selective 5-HT(6) antagonists. The synthesis, SAR, and pharmacokinetic and pharmacological activities of some of the compounds including 3-(naphthalen-1-ylsulfonyl)-5-(piperazin-1-yl)-1H-indazole (WAY-255315 or SAM-315) will be described.
Subject(s)
Indazoles/chemical synthesis , Nootropic Agents/chemical synthesis , Piperazines/chemical synthesis , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemical synthesis , Sulfones/chemical synthesis , Acetylcholine/metabolism , Animals , Biological Availability , Brain/metabolism , Glutamic Acid/metabolism , HeLa Cells , Humans , Indazoles/pharmacokinetics , Indazoles/pharmacology , Ligands , Nootropic Agents/pharmacokinetics , Nootropic Agents/pharmacology , Piperazines/pharmacokinetics , Piperazines/pharmacology , Rats , Serotonin Antagonists/pharmacokinetics , Serotonin Antagonists/pharmacology , Structure-Activity Relationship , Sulfones/pharmacokinetics , Sulfones/pharmacologyABSTRACT
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
Novel 3-(arylsulfonyl)-1-(azacyclyl)-1H-indoles 6 were synthesized as potential 5-HT(6) receptor ligands, based on constraining a basic side chain as either a piperidine or a pyrrolidine. Many of these compounds had good 5-HT(6) binding affinity with K(i) values <10nM. Depending on substitution, both agonists (e.g., 6o: EC(50)=60nM, E(max)=70%) and antagonists (6y: IC(50)=17 nM, I(max)=86%) were identified in a 5-HT(6) adenylyl cyclase assay.
Subject(s)
Indoles/chemistry , Receptors, Serotonin/chemistry , Serotonin Antagonists/chemistry , Serotonin Receptor Agonists/chemistry , Sulfones/chemistry , Humans , Indoles/chemical synthesis , Indoles/pharmacology , Ligands , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacology , Serotonin Receptor Agonists/chemical synthesis , Serotonin Receptor Agonists/pharmacology , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/pharmacologyABSTRACT
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
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
1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-pyrrolopyridines were prepared. Binding assays indicated they are 5-HT(6) receptor ligands, among which 6f and 6g showed high affinity for 5-HT(6) receptors with K(i)=3.9 and 1.7 nM, respectively.
Subject(s)
Pyridines/pharmacology , Pyrroles/pharmacology , Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology , Serotonin Receptor Agonists/pharmacology , HeLa Cells , Humans , Ligands , Pyridines/chemistry , Pyrroles/chemistry , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemistry , Serotonin Receptor Agonists/chemistryABSTRACT
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 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines 10a-z was prepared as novel 5-HT(6) ligands. The best compounds were high affinity, full agonists at 5-HT(6) receptors. Several agonists demonstrated good selectivity over other serotonergic and dopaminergic receptors. Acute administration of selective agonist 10e significantly increased extracellular GABA concentrations in rat frontal cortex. This compound also reduced adjunctive drinking behavior in the rat schedule-induced polydipsia assay, possibly predictive of efficacy in obsessive compulsive disorder and other anxiety related disorders.
Subject(s)
Cerebral Cortex/drug effects , Drinking Behavior/drug effects , Receptors, Serotonin/metabolism , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/pharmacology , Animals , Cerebral Cortex/metabolism , Glutamic Acid/analysis , Glutamic Acid/metabolism , HeLa Cells , Humans , Protein Binding , Rats , Serotonin Receptor Agonists/administration & dosage , Serotonin Receptor Agonists/chemical synthesis , gamma-Aminobutyric Acid/analysis , gamma-Aminobutyric Acid/metabolismABSTRACT
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
N1-Arylsulfonyltryptamines have been identified as 5-HT6 receptor ligands. In particular, N1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine (11q) is a high affinity, potent full agonist (5-HT6 Ki = 2 nM, EC50 = 6.5 nM, Emax = 95.5%). Compound 11q is selective in a panel of over 40 receptors and ion channels, has good pharmacokinetic profile, has been shown to increase GABA levels in the rat frontal cortex, and is active in the schedule-induced polydipsia model for obsessive compulsive disorders.
Subject(s)
Receptors, Serotonin/metabolism , Serotonin Receptor Agonists/chemical synthesis , Thiazoles/chemistry , Tryptamines/chemical synthesis , Administration, Oral , Animals , Biological Availability , CHO Cells , Cricetinae , Cricetulus , Dogs , Frontal Lobe/metabolism , Haplorhini , Humans , In Vitro Techniques , Mice , Microdialysis , Microsomes, Liver/metabolism , Radioligand Assay , Rats , Serotonin Receptor Agonists/pharmacokinetics , Serotonin Receptor Agonists/pharmacology , Solubility , Structure-Activity Relationship , Thiazoles/pharmacokinetics , Thiazoles/pharmacology , Tryptamines/chemistry , Tryptamines/pharmacokinetics , Tryptamines/pharmacology , gamma-Aminobutyric Acid/metabolismABSTRACT
1-Aminoethyl-3-arylsulfonyl-1H-indoles 1 are 5-HT(6) receptor ligands with modest activity in a 5-HT(6) cyclase assay. Introduction of an additional nitrogen in the indole ring provides 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines 2 with both enhanced 5-HT(6) affinity and cyclase activity, many acting as 5-HT(6) agonists. We constrained the basic side chain as part of a ring to make 1-(azacyclyl)-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines incorporating a pyrrolidinyl 3 or piperidinyl 4 ring system. Preparation of compounds 3 and 4 required synthesis of the key intermediates, 1-(pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridines 7 and 1-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridines 8, respectively. Intermediates 7 were prepared through alkylation of 7-azaindole while the intermediates 8 required an alternate synthesis. The compounds of both series 3 and 4 were shown to have high binding affinities for the 5-HT(6) receptor. The in vitro functional activity at the 5-HT(6) receptor varied depending on various functionalities including the selection of the arylsulfonyl, the substitution on the arylsulfonyl group, the ring size, and the substitution on the basic amine moiety producing either 5-HT(6) receptor agonists or antagonists.
Subject(s)
Pyridines/pharmacology , Receptors, Serotonin/chemistry , Serotonin Antagonists/pharmacology , Serotonin Receptor Agonists/pharmacology , Binding, Competitive , HeLa Cells/drug effects , Humans , Ligands , Molecular Structure , Pyridines/chemical synthesis , Pyridines/chemistry , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/chemistry , Serotonin Receptor Agonists/chemical synthesis , Serotonin Receptor Agonists/chemistry , Structure-Activity RelationshipABSTRACT
5-Arylsulfonylamido-3-(pyrrolidin-2-ylmethyl)-1H-indoles have been identified as high-affinity 5-HT(6) receptor ligands. Within this class, several of the (R)-enantiomers were potent agonists having EC(50) values of 1 nM or less and functioning as full agonists while the (S)-enantiomers displayed moderate antagonist activity.
