ABSTRACT
A series of isoquinuclidine benzamides as glycine uptake inhibitors for the treatment of schizophrenia are described. Potency, lipophilicity, and intrinsic human microsomal clearance were parameters for optimization. Potency correlated with the nature of the ortho substituents of the benzamide ring, and reductions in lipophilicity could be achieved through heteroatom incorporation in the benzamide and pendant phenyl moieties. Improvements in human CLint were achieved through changes in ring size and the N-alkyl group of the isoquinuclidine itself, with des-alkyl derivatives (40-41, 44) demonstrating the most robust microsomal stability. Dimethylbenzamide 9 was tested in a mouse MK801 LMA assay and had a statistically significant attenuation of locomotor activity at 3 and 10⯵mol/kg compared to control.
Subject(s)
Benzamides/pharmacology , Bridged Bicyclo Compounds/pharmacology , Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Administration, Oral , Animals , Benzamides/administration & dosage , Benzamides/chemistry , Bridged Bicyclo Compounds/administration & dosage , Bridged Bicyclo Compounds/chemistry , Dose-Response Relationship, Drug , Humans , Injections, Intravenous , Locomotion/drug effects , Male , Mice , Molecular Structure , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
The κ-opioid receptor plays a central role in mediating the response to stressful life events. Inhibiting κ-opioid receptor signaling is proposed as a mechanism for treating stress-related conditions such as depression and anxiety. Preclinical testing consistently confirms that disruption of κ-opioid signaling is efficacious in animal models of mood disorders. However, concerns about the feasibility of developing antagonists into drugs stem from an unusual pharmacodynamic property of prototypic κ-opioid receptor-selective antagonists; they inhibit receptor signaling for weeks to months after a single dose. Several fundamental questions include - is it possible to identify short-acting antagonists; is long-lasting inhibition necessary for efficacy; and is it safe to develop long-acting antagonists in the clinic. Here, we test representative compounds (AZ-ECPC, AZ-MTAB, and LY-DMPF) from three new chemical series of κ-opioid receptor ligands for long-lasting inhibition. Each compound dose-dependently reversed κ-opioid agonist-induced diuresis. However, unlike the prototypic antagonist, nBNI, which fully inhibited evoked diuresis for at least four weeks, the new compounds showed no inhibition after one week. The two compounds with greater potency and selectivity were tested in prenatally-stressed rats on the elevated plus maze, an exploration-based model of anxiety. Spontaneous exploration of open arms in the elevated plus maze was suppressed by prenatal stress and restored with both compounds. These findings indicate that persistent inhibition is not an inherent property of κ-opioid-selective antagonists and that post-stress dosing with transient inhibitors can be effective in a mood disorder model. This further supports κ-opioid receptor as a promising target for developing novel psychiatric medications.
Subject(s)
Anti-Anxiety Agents/pharmacology , Receptors, Opioid, kappa/antagonists & inhibitors , Animals , Anti-Anxiety Agents/therapeutic use , Behavior, Animal/drug effects , Diuresis/drug effects , Drug Evaluation, Preclinical , Inhibition, Psychological , Male , Maze Learning/drug effects , Rats , Rats, Sprague-Dawley , Stress, Psychological/drug therapy , Stress, Psychological/physiopathology , Time FactorsABSTRACT
Positive allosteric modulation of metabotropic glutamate receptor 5 (mGluR5) is regarded as a potential novel treatment for schizophrenic patients. Herein we report the synthesis and SAR of 4-aryl piperazine and piperidine amides as potent mGluR5 positive allosteric modulators (PAMs). Several analogs have excellent activity and desired drug-like properties. Compound 2b was further characterized as a PAM using several in vitro experiments, and produced robust activity in several preclinical animal models.
Subject(s)
Amides/chemistry , Piperazines/chemistry , Piperidines/chemistry , Receptors, Metabotropic Glutamate/chemistry , Allosteric Regulation , Amides/chemical synthesis , Amides/therapeutic use , Humans , Microsomes, Liver/metabolism , Piperazine , Receptor, Metabotropic Glutamate 5 , Receptors, Metabotropic Glutamate/metabolism , Schizophrenia/drug therapy , Structure-Activity RelationshipABSTRACT
Further structure activity relationship studies on a previously reported 8-azabicyclo[3.2.1]octan-3-yloxy-benzamide series of potent and selective kappa opioid receptor antagonists is discussed. Modification of the pendant N-substitution to include a cyclohexylurea moiety produced analogs with greater in vitro opioid and hERG selectivity such as 12 (kappa IC50=172 nM, mu:kappa ratio=93, delta:kappa ratio=>174, hERG IC50=>33 microM). Changes to the linker conformation and identity as well as to the benzamide ring moiety were also investigated.
Subject(s)
Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Benzamides/chemistry , Benzamides/pharmacology , Receptors, Opioid, kappa/antagonists & inhibitors , Receptors, Opioid, kappa/metabolism , Animals , Antidepressive Agents/chemical synthesis , Antidepressive Agents/pharmacokinetics , Benzamides/chemical synthesis , Benzamides/pharmacokinetics , Brain/metabolism , Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/pharmacokinetics , Bridged Bicyclo Compounds/pharmacology , Depressive Disorder, Major/drug therapy , Humans , Microsomes, Liver/metabolism , Rats , Structure-Activity RelationshipABSTRACT
Initial high throughput screening efforts identified highly potent and selective kappa opioid receptor antagonist 3 (κ IC(50)=77 nM; µ:κ and δ:κ IC(50) ratios>400) which lacked CNS exposure in vivo. Modification of this scaffold resulted in development of a series of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides showing potent and selectivity κ antagonism as well as good brain exposure. Analog 6c (κ IC(50)=20 nM; µ:κ=36, δ:κ=415) was also shown to reverse κ-agonist induced rat diuresis in vivo.
Subject(s)
Benzamides/chemistry , Receptors, Opioid, kappa/antagonists & inhibitors , Tropanes/chemistry , Animals , Benzamides/chemical synthesis , Benzamides/pharmacokinetics , Cell Line, Tumor , Diuresis/drug effects , Drug Evaluation, Preclinical , High-Throughput Screening Assays , Humans , Microsomes, Liver/metabolism , Rats , Receptors, Opioid, kappa/metabolism , Structure-Activity Relationship , Tropanes/chemical synthesis , Tropanes/pharmacokineticsABSTRACT
A novel series of glycine transporter 1 (GlyT1) inhibitors is described. Scoping of the heterocycle moiety of hit 4-chlorobenzenesulfonamide 1 led to replacement of the piperidine with an azepane for a modest increase in potency. Phenyl sulfonamides proved superior to alkyl and non-phenyl aromatic sulfonamides, while subsequent ortho substitution of the 2-(azepan-1-yl)-2-phenylethanamine aromatic ring yielded 39 (IC(50) 37 nM, solubility 14 microM), the most potent GlyT1 inhibitor in this series. Favorable brain-plasma ratios were observed for select compounds in pharmacokinetic studies to evaluate CNS penetration.
Subject(s)
Azetidines/chemistry , Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Sulfonamides/chemistry , Animals , Azepines/chemistry , Azetidines/chemical synthesis , Azetidines/pharmacokinetics , Brain/metabolism , Central Nervous System/metabolism , Glycine Plasma Membrane Transport Proteins/metabolism , Male , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokinetics , BenzenesulfonamidesABSTRACT
A new class of bicyclic pyrrolopyrimidine-based Janus kinase 3 (JAK-3) inhibitors are described. Many of these inhibitors showed low nanomolar activity against JAK-3.
Subject(s)
Janus Kinase 3/antagonists & inhibitors , Pyrimidines/chemical synthesis , Pyrroles/chemical synthesis , Autoimmune Diseases/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Immunity/drug effects , Janus Kinase 2/antagonists & inhibitors , Pyrimidines/pharmacology , Pyrroles/pharmacology , Structure-Activity RelationshipABSTRACT
This communication details the synthesis, biological activity, and binding mode of a novel class of 2-benzimidazole substituted pyrimidines. The most potent analogs disclosed showed low nanomolar activity for the inhibition of Lck kinase and a representative analog was co-crystallized with Hck (a structurally related member of the Src family kinases).
Subject(s)
Benzimidazoles/chemistry , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemistry , Hydrogen Bonding , Inhibitory Concentration 50 , Interleukin-2/metabolism , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/chemical synthesis , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/metabolism , Molecular Structure , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-hck/chemistry , Proto-Oncogene Proteins c-hck/metabolism , Structure-Activity RelationshipABSTRACT
This communication details the synthesis, biological activity, and proposed binding mode of a novel class of tri-cyclic derivatives of 1,2-dihydro-pyrimido[4,5-c]pyridazines 1 and 2. The most potent analogs disclosed showed low nanomolar activity for the inhibition of Lck kinase.
Subject(s)
Drug Industry/methods , Enzyme Inhibitors/pharmacology , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors , Pyridazines/chemistry , Pyrimidines/chemistry , Ribonucleosides/chemistry , Drug Design , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Lymphocytes/metabolism , Models, Chemical , Models, Molecular , Pyridazines/pharmacology , Pyrimidines/pharmacology , Structure-Activity RelationshipABSTRACT
A series of C-2, C-8, and N-9 trisubstituted purine based inhibitors of TNF-alpha production are described. The most potent analogs showed low nanomolar activity against LPS-induced TNF-alpha production in a THP-1 cell based assay. The SAR of the series was optimized with the aid of X-ray co-crystal structures of these inhibitors bound with mutated p38 (mp38).
Subject(s)
Purines/chemistry , Tumor Necrosis Factor-alpha/chemistry , Cell Line , Chemistry, Pharmaceutical , Crystallography, X-Ray , Drug Design , Humans , Lipopolysaccharides/chemistry , Models, Chemical , Models, Molecular , p38 Mitogen-Activated Protein Kinases/chemistry , p38 Mitogen-Activated Protein Kinases/geneticsABSTRACT
A new class of lymphocyte specific tyrosine kinase (lck) inhibitors based on an N-4,6-pyrimidine-N-alkyl-N'-phenyl urea scaffold is described. Many of these compounds showed low-nanomolar inhibition of lck kinase activity as well as IL-2 synthesis from Jurkat cells. One of these analogs, 7i, was shown to be orally efficacious by in vivo testing in a rat adjuvant-induced arthritis study.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors , Phenylurea Compounds/chemical synthesis , Pyrimidines/chemistry , Administration, Oral , Animals , Arthritis, Experimental/drug therapy , Arthritis, Experimental/pathology , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Humans , Interleukin-2/biosynthesis , Jurkat Cells , Molecular Structure , Phenylurea Compounds/pharmacology , RatsABSTRACT
A new class of tumor necrosis factor alpha (TNF-alpha) synthesis inhibitors based on a N-2,4-pyrimidine-N-phenyl-N'-alkyl urea scaffold is described. Many of these compounds showed low-nanomolar activity against lipopolysaccharide stimulated TNF-alpha production. Two analogs were tested in an in vivo rat iodoacetate model of osteoarthritis and shown to be orally efficacious. X-ray co-crystallization studies with mutated p38alpha showed that these trisubstituted ureas interact with the ATP-binding pocket in a pseudo-bicyclic conformation brought about by the presence of an intramolecular hydrogen bonding interaction.
Subject(s)
Arthritis, Experimental/drug therapy , Osteoarthritis/drug therapy , Phenylurea Compounds/chemistry , Phenylurea Compounds/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adenosine Triphosphate/chemistry , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/classification , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Arthritis, Experimental/chemically induced , Binding Sites , Crystallography, X-Ray , Disease Models, Animal , Drug Evaluation, Preclinical , Hydrogen Bonding , Iodoacetates , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Models, Molecular , Molecular Structure , Osteoarthritis/chemically induced , Phenylurea Compounds/classification , Pyrimidines/classification , Rats , Stereoisomerism , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
A new class of tumor necrosis factor alpha (TNF-alpha) synthesis inhibitors based on an N-2,4-pyrimidine-N-phenyl-N'-phenyl urea scaffold is described. Many of these compounds showed low-nanomolar activity against lipopolysaccharide stimulated TNF-alpha production. X-ray co-crystallization studies with mutated p38alpha showed that these trisubstituted ureas interact with the ATP-binding pocket in a pseudo-bicyclic conformation brought about by the presence of an intramolecular hydrogen bonding interaction.
Subject(s)
Phenylurea Compounds/chemistry , Phenylurea Compounds/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adenosine Triphosphate/chemistry , Binding Sites , Crystallography, X-Ray , Hydrogen Bonding , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Models, Molecular , Molecular Structure , Phenylurea Compounds/classification , Pyrimidines/classification , Stereoisomerism , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
4-Aryl-5-pyrimidyl based cytokine synthesis inhibitors that contain a novel monocyclic, pyrazolone heterocyclic core are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production. One of the compounds (6e) was found to be efficacious in the rat iodoacetate (RIA) in vivo model of osteoarthritis. The X-ray crystal structure of a pyrazolone inhibitor cocrystallized with mutated p38 (mp38) is presented.
Subject(s)
Cytokines/antagonists & inhibitors , Cytokines/biosynthesis , Pyrazolones/chemical synthesis , Pyrazolones/pharmacology , Animals , Disease Models, Animal , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Kinetics , Lipopolysaccharides/pharmacology , Models, Molecular , Molecular Conformation , Osteoarthritis/prevention & control , Pyrazolones/chemistry , Rats , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/biosynthesis , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitorsABSTRACT
4-Aryl-3-pyridyl and 4-aryl-3-pyrimidinyl based tumor necrosis factor-alpha (TNF-alpha) inhibitors, which contain a novel isoxazolone five-membered heterocyclic core are described. Many showed sub-micromolar activity against lipopolysaccharide-induced TNF-alpha production.
Subject(s)
Isoxazoles/chemical synthesis , Isoxazoles/pharmacology , Pyrimidines/chemical synthesis , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Acetaldehyde , Binding Sites , Cell Line , Humans , Lipopolysaccharides/pharmacology , Models, Molecular , Molecular Structure , Protein Conformation , Pyrimidines/pharmacology , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/chemistry , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitorsABSTRACT
4-Aryl-5-pyrimidyl-based cytokine synthesis inhibitors of TNF-alpha production, which contain a novel bicyclic pyrazole heterocyclic core, are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production in a THP-1 cell-based assay and against human p38 alpha MAP kinase in an isolated enzyme assay. The X-ray crystal structure of a bicyclic pyrazole inhibitor co-crystallized with mutated p38 (mp38) is presented.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Pyrazoles/chemical synthesis , Tumor Necrosis Factor-alpha/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Humans , Lipopolysaccharides/pharmacology , Pyrazoles/pharmacology , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/biosynthesis , p38 Mitogen-Activated Protein Kinases/chemistryABSTRACT
Novel substituted [5,5]-bicyclic pyrzazolones are presented as inhibitors of tumor necrosis factor-alpha (TNF-alpha) production. Many of these compounds show low nanomolar activity against lipopolysaccaride (LPS)-induced TNF-alpha production in THP-1 cells. This class of molecules was co-crystallized with mutated p38, and several analogs showed good oral bioavailability in the rat. Oral activity of these compounds in the rat iodoacetate model for osteoarthritis is discussed.
Subject(s)
Pyrazolones/chemistry , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Lipopolysaccharides/pharmacology , Models, Molecular , Pyrazolones/administration & dosage , Pyrazolones/pharmacokinetics , Pyrazolones/pharmacology , Rats , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
2-Aryl-3-pyrimidinyl based tumor necrosis factor-alpha (TNF-alpha) inhibitors, which contain a novel bicyclic pyrazolone core, are described. Many showed low-nanomolar activity against lipopolysaccharide-induced TNF-alpha production in monocytic cells. Secondary screening data are presented for the pyrimidinyl bicyclic pyrazolones. Several of these analogues showed good oral bioavailability in rat and efficacy in the rat iodoacetate in vivo model.
Subject(s)
Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Humans , In Vitro Techniques , Monocytes/drug effects , Monocytes/metabolism , Phosphotransferases/antagonists & inhibitors , Phosphotransferases/metabolism , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Rats , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
A number of highly functionalized dioxocyclams with acetic acid side chains on the secondary amine sites and ethylene glycol side chains on 6 and 13-positions (12a, 12b) or a tetra(ethylene glycol) side chain linking the 6 and 13 positions (15) were synthesized and characterized, as was a bis-dioxocyclam bridged across the 6 and 13 positions by tetra(ethylene glycol) groups (16). These were screened for their ability to complex Gd3+. Only ligands 15 and 16, having tetra(ethylene glycol) groups, formed such complexes.
