RESUMEN
To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor-induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2 adrenergic signaling, a pathway known to be antinociceptive in humans.
Asunto(s)
Neuralgia/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Fenómenos Electrofisiológicos/efectos de los fármacos , Técnicas de Inactivación de Genes , Células HEK293 , Humanos , Masculino , Ratones , Neuralgia/metabolismo , Neuralgia/fisiopatología , Nocicepción/efectos de los fármacos , Fenotipo , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/deficiencia , Proteínas Serina-Treonina Quinasas/genética , Ratas , Médula Espinal/efectos de los fármacos , Médula Espinal/enzimología , Médula Espinal/fisiopatologíaRESUMEN
Modulating GPR88 activity is suggested to have therapeutic utility in the treatment of CNS disorders, such as schizophrenia. This Letter will describe the discovery and SAR development of a class of potent GPR88 agonists.
Asunto(s)
Amidas/farmacología , Aminas/farmacología , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Descubrimiento de Drogas , Receptores Acoplados a Proteínas G/agonistas , Amidas/síntesis química , Amidas/química , Aminas/síntesis química , Aminas/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Small molecule modulators of GPR88 activity (agonists, antagonists, or modulators) are of interest as potential agents for the treatment of a variety of psychiatric disorders including schizophrenia. A series of phenylglycinol and phenylamine analogs have been prepared and evaluated for their GPR88 agonist activity and pharmacokinetic (PK) properties.
Asunto(s)
Aminas/farmacología , Diseño de Fármacos , Etanolaminas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Aminas/síntesis química , Aminas/química , Relación Dosis-Respuesta a Droga , Etanolaminas/síntesis química , Etanolaminas/química , Células HEK293 , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Programmed death-ligand 1 is a glycoprotein expressed on antigen presenting cells, hepatocytes, and tumors which upon interaction with programmed death-1, results in inhibition of antigen-specific T cell responses. Here, we report a mechanism of inhibiting programmed death-ligand 1 through small molecule-induced dimerization and internalization. This represents a mechanism of checkpoint inhibition, which differentiates from anti-programmed death-ligand 1 antibodies which function through molecular disruption of the programmed death 1 interaction. Testing of programmed death ligand 1 small molecule inhibition in a humanized mouse model of colorectal cancer results in a significant reduction in tumor size and promotes T cell proliferation. In addition, antigen-specific T and B cell responses from patients with chronic hepatitis B infection are significantly elevated upon programmed death ligand 1 small molecule inhibitor treatment. Taken together, these data identify a mechanism of small molecule-induced programmed death ligand 1 internalization with potential therapeutic implications in oncology and chronic viral infections.
Asunto(s)
Antígeno B7-H1/metabolismo , Endocitosis , Inhibidores de Puntos de Control Inmunológico/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Antineoplásicos/farmacología , Antivirales/farmacología , Células CHO , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/patología , Cricetulus , Modelos Animales de Enfermedad , Femenino , Virus de la Hepatitis B/efectos de los fármacos , Humanos , Ratones Endogámicos C57BL , Receptor de Muerte Celular Programada 1/metabolismo , Multimerización de Proteína/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
A multifunctional magnetic composite (0.3Ma-MgMnLDO-a) with the function of Cd2+ adsorption and paracetamol (PAM) degradation was successfully fabricated. Surface morphology showed that Fe3O4 agglomeration was overcome on composite. The composite had high specific surface area of 105.32â¯m2â¯g-1 and saturation magnetization of 40 emuâg-1. 0.3Ma-MgMnLDO-a could reach Cd2+ adsorption equilibrium within 5â¯min with 99 % removal rate. The maximum adsorption capacity was 3.76â¯mmol·g-1 (422.62â¯mgâ¯g-1), which apparently higher than that of Fe3O4-a and MgMnLDO-a, indicating that the Fe/Mn synergism results in excellent ability for Cd2+ adsorption. Moreover, the composite could efficiently activate peroxymonosulfate (PMS) to rapid degrade PAM with the highest first-order rate constants (kobsâ¯=â¯0.116â¯min-1) and total organic carbon (TOC) removal rate (67.7 %), which also due to the contribution of Fe/Mn synergism in PMS activation. The cycling of MnIII/MnIV and FeII/FeIII played an important role in activating PMS to generateO2-â¢, 1O2 and OH for degradation. The composite exhibited both stable adsorption and catalytic performance on wide pH (3-9) and five reuse cycles. Notably, there was mutual promotion between Cd2+ and PAM adsorption, while the coexistence of Cd2+ had slight inhibition on PAM degradation. Overall, the magnetic composite had promising application for purifying heavy metals and pharmaceuticals.
Asunto(s)
Acetaminofén/química , Óxido Ferrosoférrico/química , Metales Pesados/química , Óxidos/química , Contaminantes Químicos del Agua/química , Purificación del Agua/métodos , Adsorción , Fenómenos Magnéticos , Peróxidos/química , Contaminación del AguaRESUMEN
A novel, highly potent, orally active, nonsteroidal tissue selective androgen receptor (AR) modulator (BMS-564929) has been identified, and this compound has been advanced to clinical trials for the treatment of age-related functional decline. BMS-564929 is a subnanomolar AR agonist in vitro, is highly selective for the AR vs. other steroid hormone receptors, and exhibits no significant interactions with SHBG or aromatase. Dose response studies in castrated male rats show that BMS-564929 is substantially more potent than testosterone (T) in stimulating the growth of the levator ani muscle, and unlike T, highly selective for muscle vs. prostate. Key differences in the binding interactions of BMS-564929 with the AR relative to the native hormones were revealed through x-ray crystallography, including several unique contacts located in specific helices of the ligand binding domain important for coregulatory protein recruitment. Results from additional pharmacological studies effectively exclude alternative mechanistic contributions to the observed tissue selectivity of this unique, orally active androgen. Because concerns regarding the potential hyperstimulatory effects on prostate and an inconvenient route of administration are major drawbacks that limit the clinical use of T, the potent oral activity and tissue selectivity exhibited by BMS-564929 are expected to yield a clinical profile that provides the demonstrated beneficial effects of T in muscle and other tissues with a more favorable safety window.
Asunto(s)
Imidazoles/síntesis química , Imidazoles/farmacología , Músculo Esquelético/efectos de los fármacos , Próstata/efectos de los fármacos , Pirroles/síntesis química , Pirroles/farmacología , Receptores Androgénicos/metabolismo , Testosterona/análogos & derivados , Envejecimiento/metabolismo , Animales , Aromatasa/metabolismo , Unión Competitiva , División Celular/efectos de los fármacos , Línea Celular Tumoral , Cristalografía por Rayos X , Dihidrotestosterona/química , Dihidrotestosterona/metabolismo , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Humanos , Imidazoles/metabolismo , Ligandos , Hormona Luteinizante/sangre , Masculino , Músculo Esquelético/fisiología , Orquiectomía , Próstata/fisiología , Estructura Terciaria de Proteína , Pirroles/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Androgénicos/química , Receptores Androgénicos/genética , Testosterona/química , Testosterona/metabolismo , Transcripción Genética/fisiologíaRESUMEN
Replacement of the 3-oxo group of 2-chloro-4-[(7R,7aS)-7-hydroxy-1,3-dioxotetrahydro-1H-pyrrolo[1,2c]imidazol-2(3H)-yl]-3-methylbenzonitrile resulted in a sulfamide series of selective androgen receptor modulator (SARM) agonists.
Asunto(s)
Andrógenos , Congéneres de la Testosterona/síntesis química , Congéneres de la Testosterona/farmacología , Tiadiazoles/síntesis química , Tiadiazoles/farmacología , Animales , Relación Dosis-Respuesta a Droga , Masculino , Estructura Molecular , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/crecimiento & desarrollo , Próstata/efectos de los fármacos , Próstata/crecimiento & desarrollo , Unión Proteica , Ratas , Receptores Androgénicos/metabolismo , Relación Estructura-ActividadRESUMEN
Pharmacokinetic studies in cynomolgus monkeys with a novel prototype selective androgen receptor modulator revealed trace amounts of an aniline fragment released through hydrolytic metabolism. This aniline fragment was determined to be mutagenic in an Ames assay. Subsequent concurrent optimization for target activity and avoidance of mutagenicity led to the identification of a pharmacologically superior clinical candidate without mutagenic potential.
Asunto(s)
Antagonistas de Andrógenos/química , Antagonistas de Andrógenos/síntesis química , Química Farmacéutica/métodos , Hidantoínas/química , Hidantoínas/síntesis química , Receptores Androgénicos/metabolismo , Antagonistas de Andrógenos/farmacología , Animales , Diseño de Fármacos , Escherichia coli/metabolismo , Genes Reporteros , Cinética , Macaca fascicularis , Modelos Químicos , Conformación Molecular , Mutagénesis , Mutágenos , Relación Estructura-ActividadRESUMEN
In a continuing effort to discover novel chemotypes as potent and selective PDE5 inhibitors for the treatment of male erectile dysfunction (ED), we have found that 4-benzylaminoquinoline derivatives are very potent and selective PDE5 inhibitors. Some compounds in this series had PDE5 IC(50)'s as low as 50 pM. While an electron withdrawing group at the C6-position of the quinoline substantially improved PDE5 potency, an ethyl group at the C8-position not only improved the PDE5 potency but also the isozyme selectivity. Substitutents at the C3-position can incorporate a variety of different groups. The synthesis and primary structure-activity relationship of this new series of potent PDE5 inhibitors are described.