RESUMEN
A series of substituted pyridines, ether linked to a phenylpiperidine core were optimized for dual NK(1)/SERT affinity. Optimization based on NK(1)/SERT binding affinities, and minimization of off-target ion channel activity lead to the discovery of compound 44. In vivo evaluation of 44 in the gerbil forced swim test (a depression model), and ex-vivo NK(1)/SERT receptor occupancy data support the potential of a dual acting compound for the treatment of depression.
Asunto(s)
Depresión/tratamiento farmacológico , Diseño de Fármacos , Antagonistas del Receptor de Neuroquinina-1 , Piridinas/síntesis química , Antagonistas de la Serotonina , Animales , Modelos Animales de Enfermedad , Gerbillinae , Concentración 50 Inhibidora , Estructura Molecular , Piridinas/química , Piridinas/uso terapéutico , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/uso terapéuticoRESUMEN
A series of (N-benzyl-N-phenylsulfonamido)alkyl amides were developed from classic and parallel synthesis strategies. Compounds with good in vitro and in vivo γ-secretase activity were identified and described.
Asunto(s)
Amidas/química , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores de Proteasas/química , Sulfonamidas/química , Amidas/síntesis química , Amidas/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Fragmentos de Péptidos/metabolismo , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/metabolismo , Unión Proteica , Relación Estructura-ActividadRESUMEN
Based on a favorable balance between CRF-R1 affinity, lipophilicity and metabolic stability, compound 10 was evaluated for potential development as PET radioligand. Compound [(18)F]10 was prepared with high radiochemical purity and showed promising binding properties in rat brain imaging experiments.
Asunto(s)
Compuestos de Anilina/química , Radioisótopos de Flúor , Tomografía de Emisión de Positrones , Pirazinas/química , Pirazoles/química , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Radioisótopos de Flúor/sangre , Imagenología Tridimensional , Estructura Molecular , Pirazoles/metabolismo , Ratas , Distribución TisularRESUMEN
Heterocyclic replacement of the isophthalamide phenyl ring in hydroxyethylamine (HEA) BACE-1 inhibitors was explored. A variety of indole-1,3-dicarboxamide HEAs exhibited potent BACE-1 enzyme inhibition, but displayed poor cellular activity. Improvements in cellular activity and aspartic protease selectivity were observed for 7-azaindole-1,3-dicarboxamide HEAs. A methylprolinol-bearing derivative (10n) demonstrated robust reductions in rat plasma Aß levels, but did not lower rat brain Aß due to poor central exposure. The same analog exhibited a high efflux ratio in a bidirectional Caco-2 assay and was likely a substrate of the efflux transporter P-glycoprotein. X-ray crystal structures are reported for two indole HEAs in complex with BACE-1.
Asunto(s)
Aminas/química , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Indoles/síntesis química , Inhibidores de Proteasas/química , Piridinas/síntesis química , Aminas/síntesis química , Aminas/farmacología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/sangre , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Sitios de Unión , Cristalografía por Rayos X , Indoles/química , Indoles/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Estructura Terciaria de Proteína , Piridinas/química , Piridinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
The synthesis and gamma-secretase inhibition data for a series of nitrogen-appended N-alkylsulfonamides (11-47) are described. Inhibition of brain Abeta in transgenic mice was demonstrated by two of these compounds (23 and 44).
Asunto(s)
Aminas/química , Aminas/farmacología , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Sulfonamidas/química , Sulfonamidas/farmacología , Alquilación , Aminas/síntesis química , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Animales , Azoles/síntesis química , Azoles/química , Azoles/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Encéfalo/metabolismo , Interacciones Hidrofóbicas e Hidrofílicas , Concentración 50 Inhibidora , Ratones , Ratones Transgénicos , Fragmentos de Péptidos/metabolismo , Inhibidores de Proteasas/síntesis química , Relación Estructura-Actividad , Sulfonamidas/síntesis químicaRESUMEN
The known interactions between the serotonergic and neurokinin systems suggest that serotonin reuptake inhibitor (SSRIs) efficacy may be improved by neurokinin-1 receptor (NK1R) antagonism. In the current studies combination of a subeffective dose of an SSRI (0.3 mg/kg fluoxetine or 0.03 mg/kg citalopram) with a subeffective dose of an NK1R antagonist (0.3 mg/kg aprepitant or 1 mg/kg CP-122,721) produced efficacy in the gerbil forced swim test (FST). Serotonin transporter (SERT) occupancy produced by 1 mg/kg fluoxetine (lowest efficacious dose) was 52 ± 5% and was reduced to 29 ± 4% at 0.3 mg/kg, a dose that was efficacious in combination with 0.3 mg/kg aprepitant or 1 mg/kg CP-122,721; the corresponding NK1R occupancies were 79 ± 4% and 61 ± 4% for aprepitant and CP-122,721, respectively. For citalopram, SERT occupancy at the lowest efficacious dose (0.1 mg/kg) was 50 ± 4% and was reduced to 20 ± 5% at 0.03 mg/kg, a dose that was efficacious when combined with aprepitant (0.3 mg/kg). Aprepitant (10 mg/kg) augmented the serotonin elevation produced by fluoxetine (1 or 10 mg/kg) in the gerbil prefrontal cortex; i.e. NK1R antagonism can modulate serotonin responses. A novel orally-available dual-acting NK1R antagonist/SERT inhibitor BMS-795176 is described; gerbil Ki = 1.4 and 1 nM at NK1R and SERT, respectively. BMS-795176 was efficacious in the gerbil FST; efficacy was observed with 35 ± 3% SERT occupancy and 73 ± 3% NK1R occupancy. The interaction between NK1R antagonism and SERT inhibition to lower the SERT occupancy required for antidepressant-like efficacy suggests that BMS-795176 has the potential to improve efficacy with a reduction in SSRI-associated side effects.
Asunto(s)
Citalopram/farmacología , Fluoxetina/farmacología , Morfolinas/farmacología , Piperidinas/farmacología , Receptores de Neuroquinina-1/metabolismo , Animales , Antidepresivos/farmacología , Aprepitant , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Gerbillinae , Células HEK293 , Humanos , Pérdida de Tono Postural/efectos de los fármacos , Masculino , Antagonistas del Receptor de Neuroquinina-1/farmacología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ensayo de Unión Radioligante , Serotonina/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
During the course of our research efforts to develop a potent and selective γ-secretase inhibitor for the treatment of Alzheimer's disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-ß precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compound 4 is a potent inhibitor of γ-secretase (Aß40 IC50 = 0.30 nM), demonstrating a 193-fold selectivity against Notch. Oral administration of 4 significantly reduced Aß40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs.
RESUMEN
A series of N-alkylbenzenesulfonamides were developed from a high throughput screening hit. Classic and parallel synthesis strategies were employed to produce compounds with good in vitro and in vivo gamma-secretase activity.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Sulfonamidas/química , Sulfonamidas/farmacología , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ratones , Ratones Transgénicos , Estructura Molecular , Unión ProteicaRESUMEN
A series of amino-caprolactam sulfonamides were developed from a screening hit. Compounds with good in vitro and in vivo gamma-secretase activity are reported.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Caprolactama/farmacología , Inhibidores Enzimáticos/farmacología , Caprolactama/química , Inhibidores Enzimáticos/químicaRESUMEN
A series of fluoren-9-yl ethyl amides (2) were synthesized and evaluated for human melatonin MT(1) and MT(2) receptor binding. N-[2-(2,7-dimethoxyfluoren-9-yl)ethyl]propanamide (2b) was selected and evaluated in functional assays measuring intrinsic activity at the human MT(1) and MT(2) receptors and demonstrated full agonism at both receptors. The chronobiotic properties of 2b were demonstrated in both acute and chronic rat models where 2b produced an acute phase advance of 32 min at 1mg/kg and chronically entrained free-running rats with a mean effective dose of 0.23 mg/kg. Compound 2b is significantly less efficacious than melatonin in constricting human coronary artery.
Asunto(s)
Fenómenos Cronobiológicos/fisiología , Fluorenos/química , Melatonina/metabolismo , Amidas/síntesis química , Amidas/farmacología , Animales , Sitios de Unión , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Células 3T3 NIH , Ensayo de Unión Radioligante , Ratas , Receptores de Melatonina/metabolismo , Relación Estructura-ActividadRESUMEN
Using a cell-based assay, we have identified optimal residues and key recognition elements necessary for inhibition of gamma-secretase. An (S)-hydroxy group or 3,5-difluorophenylacetyl group at the amino terminus and N-methyltertiary amide moiety at the carboxy terminus provided potent gamma-secretase inhibitors with an IC(50) <10 nM.