RESUMEN
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.
Asunto(s)
Benzamidas/farmacología , Compuestos Bicíclicos con Puentes/farmacología , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Administración Oral , Animales , Benzamidas/administración & dosificación , Benzamidas/química , Compuestos Bicíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos con Puentes/química , Relación Dosis-Respuesta a Droga , Humanos , Inyecciones Intravenosas , Locomoción/efectos de los fármacos , Masculino , Ratones , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Ansiolíticos/farmacología , Receptores Opioides kappa/antagonistas & inhibidores , Animales , Ansiolíticos/uso terapéutico , Conducta Animal/efectos de los fármacos , Diuresis/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Inhibición Psicológica , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/fisiopatología , Factores de TiempoRESUMEN
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.
Asunto(s)
Amidas/química , Piperazinas/química , Piperidinas/química , Receptores de Glutamato Metabotrópico/química , Regulación Alostérica , Amidas/síntesis química , Amidas/uso terapéutico , Humanos , Microsomas Hepáticos/metabolismo , Piperazina , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/metabolismo , Esquizofrenia/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antidepresivos/química , Antidepresivos/farmacología , Benzamidas/química , Benzamidas/farmacología , Receptores Opioides kappa/antagonistas & inhibidores , Receptores Opioides kappa/metabolismo , Animales , Antidepresivos/síntesis química , Antidepresivos/farmacocinética , Benzamidas/síntesis química , Benzamidas/farmacocinética , Encéfalo/metabolismo , Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Bicíclicos con Puentes/química , Compuestos Bicíclicos con Puentes/farmacocinética , Compuestos Bicíclicos con Puentes/farmacología , Trastorno Depresivo Mayor/tratamiento farmacológico , Humanos , Microsomas Hepáticos/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Benzamidas/química , Receptores Opioides kappa/antagonistas & inhibidores , Tropanos/química , Animales , Benzamidas/síntesis química , Benzamidas/farmacocinética , Línea Celular Tumoral , Diuresis/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Ensayos Analíticos de Alto Rendimiento , Humanos , Microsomas Hepáticos/metabolismo , Ratas , Receptores Opioides kappa/metabolismo , Relación Estructura-Actividad , Tropanos/síntesis química , Tropanos/farmacocinéticaRESUMEN
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.
Asunto(s)
Azetidinas/química , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Sulfonamidas/química , Animales , Azepinas/química , Azetidinas/síntesis química , Azetidinas/farmacocinética , Encéfalo/metabolismo , Sistema Nervioso Central/metabolismo , Proteínas de Transporte de Glicina en la Membrana Plasmática/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacocinética , BencenosulfonamidasRESUMEN
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.
Asunto(s)
Janus Quinasa 3/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirroles/síntesis química , Enfermedades Autoinmunes/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Inmunidad/efectos de los fármacos , Janus Quinasa 2/antagonistas & inhibidores , Pirimidinas/farmacología , Pirroles/farmacología , Relación Estructura-ActividadRESUMEN
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).
Asunto(s)
Bencimidazoles/química , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/química , Enlace de Hidrógeno , Concentración 50 Inhibidora , Interleucina-2/metabolismo , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/síntesis química , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/metabolismo , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-hck/química , Proteínas Proto-Oncogénicas c-hck/metabolismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Industria Farmacéutica/métodos , Inhibidores Enzimáticos/farmacología , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Piridazinas/química , Pirimidinas/química , Ribonucleósidos/química , Diseño de Fármacos , Inhibidores Enzimáticos/química , Humanos , Concentración 50 Inhibidora , Linfocitos/metabolismo , Modelos Químicos , Modelos Moleculares , Piridazinas/farmacología , Pirimidinas/farmacología , Relación Estructura-ActividadRESUMEN
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).
Asunto(s)
Purinas/química , Factor de Necrosis Tumoral alfa/química , Línea Celular , Química Farmacéutica , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Lipopolisacáridos/química , Modelos Químicos , Modelos Moleculares , Proteínas Quinasas p38 Activadas por Mitógenos/química , Proteínas Quinasas p38 Activadas por Mitógenos/genéticaRESUMEN
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.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Compuestos de Fenilurea/síntesis química , Pirimidinas/química , Administración Oral , Animales , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/patología , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Interleucina-2/biosíntesis , Células Jurkat , Estructura Molecular , Compuestos de Fenilurea/farmacología , RatasRESUMEN
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.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Osteoartritis/tratamiento farmacológico , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adenosina Trifosfato/química , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/clasificación , Antiinflamatorios no Esteroideos/farmacología , Artritis Experimental/inducido químicamente , Sitios de Unión , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Enlace de Hidrógeno , Yodoacetatos , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Modelos Moleculares , Estructura Molecular , Osteoartritis/inducido químicamente , Compuestos de Fenilurea/clasificación , Pirimidinas/clasificación , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
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.
Asunto(s)
Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adenosina Trifosfato/química , Sitios de Unión , Cristalografía por Rayos X , Enlace de Hidrógeno , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Modelos Moleculares , Estructura Molecular , Compuestos de Fenilurea/clasificación , Pirimidinas/clasificación , Estereoisomerismo , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
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.
Asunto(s)
Citocinas/antagonistas & inhibidores , Citocinas/biosíntesis , Pirazolonas/síntesis química , Pirazolonas/farmacología , Animales , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Cinética , Lipopolisacáridos/farmacología , Modelos Moleculares , Conformación Molecular , Osteoartritis/prevención & control , Pirazolonas/química , Ratas , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/biosíntesis , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidoresRESUMEN
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.
Asunto(s)
Isoxazoles/síntesis química , Isoxazoles/farmacología , Pirimidinas/síntesis química , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Acetaldehído , Sitios de Unión , Línea Celular , Humanos , Lipopolisacáridos/farmacología , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Pirimidinas/farmacología , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/química , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidoresRESUMEN
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.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Pirazoles/síntesis química , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Humanos , Lipopolisacáridos/farmacología , Pirazoles/farmacología , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/biosíntesis , Proteínas Quinasas p38 Activadas por Mitógenos/químicaRESUMEN
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.
Asunto(s)
Pirazolonas/química , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Lipopolisacáridos/farmacología , Modelos Moleculares , Pirazolonas/administración & dosificación , Pirazolonas/farmacocinética , Pirazolonas/farmacología , Ratas , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
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.
Asunto(s)
Pirazoles/síntesis química , Pirimidinas/síntesis química , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Humanos , Técnicas In Vitro , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Fosfotransferasas/antagonistas & inhibidores , Fosfotransferasas/metabolismo , Pirazoles/química , Pirazoles/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
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.