RESUMEN
γ-Secretase is an intramembrane cleaving protease that is responsible for the generation of amyloid-ß peptides, which are linked to the pathogenesis of Alzheimer disease. Recently, γ-secretase modulators (GSMs) have been shown to specifically decrease production of the aggregation-prone and toxic longer Aß species, and concomitantly increase the levels of shorter Aß. We previously found that phenylimidazole-type GSMs bind to presenilin 1 (PS1), the catalytic subunit of the γ-secretase, and allosterically modulate γ-secretase activity. However, the precise conformational alterations in PS1 remained unclear. Here we mapped the amino acid residues in PS1 that is crucial for the binding and pharmacological actions of E2012, a phenylimidazole-type GSM, using photoaffinity labeling and the substituted cysteine accessibility method. We also demonstrated that a piston-like vertical motion of transmembrane domain (TMD) 1 occurs during modulation of Aß production. Taking these results together, we propose a model for the molecular mechanism of phenylimidazole-type GSMs, in which the trimming activity of γ-secretase is modulated by the position of the TMD1 of PS1 in the lipid bilayer.SIGNIFICANCE STATEMENT Reduction of the toxic longer amyloid-ß peptide is one of the therapeutic approaches for Alzheimer disease. A subset of small compounds called γ-secretase modulators specifically decreases the longer amyloid-ß production, although its mechanistic action remains unclear. Here we found that the modulator compound E2012 targets to the hydrophilic loop 1 of presenilin 1, which is a catalytic subunit of the γ-secretase. Moreover, E2012 triggers the piston movement of the transmembrane domain 1 of presenilin 1, which impacts on the γ-secretase activity. These results illuminate how γ-secretase modulators allosterically affect the proteolytic activity, and highlight the importance of the structural dynamics of presenilin 1 in the complexed process of the intramembrane cleavage.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/química , Precursor de Proteína beta-Amiloide/metabolismo , Modelos Químicos , Presenilina-1/química , Secuencia de Aminoácidos , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Benzofenonas/metabolismo , Sitios de Unión , Biotina/análogos & derivados , Biotina/metabolismo , Femenino , Humanos , Imidazoles/metabolismo , Membrana Dobles de Lípidos , Masculino , Ratones , Microsomas/metabolismo , Movimiento (Física) , Mutación , Etiquetas de Fotoafinidad , Piperidinas/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo , Unión Proteica , Dominios Proteicos , Procesamiento Proteico-Postraduccional , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismoRESUMEN
The first total synthesis of RQN-18690A (18-deoxyherboxidiene) and the determination of its absolute stereochemical configuration are described. The synthesis features an organocatalytic aldol reaction for the first step, 1,4- and 1,2- dual reductions of α,ß-unsaturated δ-lactone followed by a domino reaction in a one-pot operation, and diastereoselective epoxidation with kinetic resolution.
RESUMEN
The orexin/hypocretin receptors are a family of G protein-coupled receptors and consist of orexin-1 (OX1) and orexin-2 (OX2) receptor subtypes. Orexin receptors are expressed throughout the central nervous system and are involved in the regulation of the sleep/wake cycle. Because modulation of these receptors constitutes a promising target for novel treatments of disorders associated with the control of sleep and wakefulness, such as insomnia, the development of orexin receptor antagonists has emerged as an important focus in drug discovery research. Here, we report the design, synthesis, characterization, and structure-activity relationships (SARs) of novel orexin receptor antagonists. Various modifications made to the core structure of a previously developed compound (-)-5, the lead molecule, resulted in compounds with improved chemical and pharmacological profiles. The investigation afforded a potential therapeutic agent, (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006), an orally active, potent orexin antagonist. The efficacy was demonstrated in mice in an in vivo study by using sleep parameter measurements.
Asunto(s)
Amidas/química , Aminopiridinas/farmacología , Ciclopropanos/química , Diseño de Fármacos , Descubrimiento de Drogas , Antagonistas de los Receptores de Orexina , Pirimidinas/farmacología , Administración Oral , Aminopiridinas/administración & dosificación , Animales , Calcio/metabolismo , Células Cultivadas , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Estructura Molecular , Receptores de Orexina/metabolismo , Pirimidinas/administración & dosificación , Relación Estructura-ActividadRESUMEN
Herein we describe the design, synthesis, and structure-activity relationships (SARs) of a novel phenylcyclopropane series represented by 7 and 33 b as antagonists of orexin 1 and orexin 2 receptors. With 4 serving as the initial lead for the development of orexin antagonists, exploration of SAR resulted in improved binding affinity for orexin 1 and orexin 2 receptors. Among the synthesized compounds, 33 b ((-)-N-(5-cyanopyridin-2-yl)-2-[(3,4-dimethoxyphenyl)oxymethyl]-2-phenylcyclopropanecarboxamide) exhibited potent in vitro activity and oral efficacy in animal sleep measurement experiments. The results of our study suggest that compound 33 b may serve as a valuable template for the development of new orexin receptor antagonists.
Asunto(s)
Ciclopropanos/química , Ciclopropanos/farmacología , Antagonistas de los Receptores de Orexina , Animales , Ciclopropanos/síntesis química , Ciclopropanos/farmacocinética , Diseño de Fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Receptores de Orexina/metabolismo , Sueño/efectos de los fármacos , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
Dysfunction of glutamatergic neurotransmission has been implicated in the pathogenesis of epilepsy and numerous other neurological diseases. Here we describe the discovery of a series of 1,3,5-triaryl-1H-pyridin-2-one derivatives as noncompetitive antagonists of AMPA-type ionotropic glutamate receptors. The structure-activity relationships for this series of compounds were investigated by manipulating individual aromatic rings located at positions 1, 3, and 5 of the pyridone ring. This culminated in the discovery of 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile (perampanel, 6), a novel, noncompetitive AMPA receptor antagonist that showed potent activity in an in vitro AMPA-induced Ca2+ influx assay (IC50=60 nM) and in an in vivo AMPA-induced seizure model (minimum effective dose of 2 mg/kg po). Perampanel is currently in regulatory submission for partial-onset seizures associated with epilepsy.
Asunto(s)
Descubrimiento de Drogas , Piridonas/química , Piridonas/farmacología , Receptores AMPA/antagonistas & inhibidores , Animales , Disponibilidad Biológica , Semivida , Ensayos Analíticos de Alto Rendimiento , Técnicas In Vitro , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Nitrilos , Piridonas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
We previously reported a series of 8-methyl-2-aryl-5-alkylaminoquinolines as a novel class of corticotropin-releasing factor-1 (CRF(1)) receptor antagonists. A critical issue encountered for this series of compounds was low aqueous solubility at physiological pH (pH 7.4). To address this issue, derivatization at key sites (R(2), R(3), R(5), R(5'), and R(8)) was performed and the relationships between structure and solubility were examined. As a result, it was revealed that introduction of a methoxy substituent at the C(8) position had a positive impact on the solubility of the derivatives. Consequently, through in vivo and in vitro biological studies, compound 21d was identified as a potent, orally active CRF(1) receptor antagonist with improved physicochemical properties.
Asunto(s)
Aminoquinolinas/química , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Administración Oral , Aminoquinolinas/síntesis química , Aminoquinolinas/farmacocinética , Animales , Conducta Animal/efectos de los fármacos , Diseño de Fármacos , Semivida , Concentración de Iones de Hidrógeno , Ratones , Ratones Endogámicos BALB C , Ratas , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Solubilidad , Relación Estructura-ActividadRESUMEN
This paper describes the design, synthesis, and structure-activity relationships of a novel series of 7-dialkylamino-3-phenyl-6-methoxy pyrazolo[5,1-b]thiazole derivatives for use as selective antagonists of the corticotropin-releasing factor 1 (CRF(1)) receptor. The most promising compound, N-butyl-3-[4-(ethoxymethyl)-2,6-dimethoxyphenyl]-6-methoxy-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[5,1-b][1,3]thiazole-7-amine (6t), showed high affinity (IC(50) = 70 nM) and functional antagonism (IC(50) = 7.1 nM) for the human CRF(1) receptor as well as dose-dependent inhibition of the CRF-induced increase in the plasma adrenocorticotropic hormone (ACTH) concentration at a dose of 30 mg/kg (po). Further, in the light/dark test in mice, the compound 6t showed anxiolytic activity at a dose of 30 mg/kg (po).
Asunto(s)
Ansiolíticos/síntesis química , Pirazoles/síntesis química , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Tiazoles/síntesis química , Administración Oral , Hormona Adrenocorticotrópica/sangre , Animales , Ansiolíticos/química , Ansiolíticos/farmacología , Línea Celular Tumoral , Hormona Liberadora de Corticotropina/farmacología , AMP Cíclico/metabolismo , Defecación/efectos de los fármacos , Diseño de Fármacos , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Pirazoles/química , Pirazoles/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Endogámicas F344 , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacologíaRESUMEN
We designed and synthesized a series of 2-Ar-8-methyl-5-alkylaminolquinolines as potent corticotropin-releasing factor 1 (CRF(1)) receptor antagonists. The structure-activity relationships of substituents at each position (R(3), R(5), R(5'), and R(8)) was investigated. By derivatization, three compounds (6, 14b, and 14c) were identified as orally active CRF(1) receptor antagonists.
Asunto(s)
Quinolinas/química , Quinolinas/farmacología , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Administración Oral , Animales , Depresión/tratamiento farmacológico , Diseño de Fármacos , Células HEK293 , Humanos , Modelos Moleculares , Quinolinas/administración & dosificación , Quinolinas/síntesis química , Ratas , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Relación Estructura-ActividadRESUMEN
A series of 5-alkylaminolquinolines was designed and synthesized as potential novel CRF(1) receptor antagonists. The structure-activity relationships (SARs) of the substituents on each position (R(2), R(3), R(5) and R(5')) were investigated.
Asunto(s)
Quinolinas/síntesis química , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Alquilación , Aminación , Diseño de Fármacos , Células HEK293 , Humanos , Modelos Moleculares , Estructura Molecular , Quinolinas/farmacología , Relación Estructura-ActividadRESUMEN
Design, synthesis, and structure-activity relationships of a series of 3-dialkylamino-7-phenyl pyrazolo[1,5-a]pyridines (I) as selective antagonists of the corticotropin-releasing factor 1 (CRF(1)) receptor are described. The most prominent compound to emerge from this work, 46 (E2508), exhibits potent in vitro activity, excellent drug-like properties, and robust oral efficacy in animal models of stress-related disorders. It has advanced into clinical trials.
Asunto(s)
Antidepresivos/síntesis química , Pirazoles/síntesis química , Piridinas/síntesis química , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Administración Oral , Animales , Antidepresivos/farmacocinética , Antidepresivos/farmacología , Disponibilidad Biológica , AMP Cíclico/biosíntesis , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Microsomas Hepáticos/metabolismo , Pirazoles/farmacocinética , Pirazoles/farmacología , Piridinas/farmacocinética , Piridinas/farmacología , Relación Estructura-ActividadRESUMEN
A one-pot primary aminomethylation of aryl halides, triflates, mesylates, and tosylates via Suzuki-Miyaura cross-coupling reactions with sodium phthalimidomethyltrifluoroborate followed by deamidation with ethylenediamine is reported.
Asunto(s)
Boratos/química , Etilenodiaminas/química , Hidrocarburos Halogenados/química , Mesilatos/química , Paladio/química , Compuestos de Tosilo/química , Catálisis , Estructura Molecular , Sodio/químicaRESUMEN
Suzuki-Miyaura cross-coupling reactions of aryl halides and triflates with potassium acetoxymethyltrifluoroborate afforded the corresponding aryl and heteroaryl methanol products in moderate to excellent yields.
Asunto(s)
Compuestos de Bromina/química , Compuestos de Cloro/química , Mesilatos/química , Compuestos Organometálicos/química , Paladio/química , Catálisis , Hidrogenación , Ligandos , Metilación , Estructura Molecular , PotasioRESUMEN
We present efficient syntheses of serofendic acids A and B (SA-A and SA-B), novel neuroprotective substances isolated from fetal calf serum. Biological and pharmacological evaluation showed that SA-A and SA-B have potent protective action against glutamate-induced neurotoxicity, but do not interact directly with glutamate receptors. A pharmacokinetic study showed that they have good oral bioavailability in rats. The results indicate that SA-A and SA-B are potential lead compounds for candidate drugs to treat various neurological disorders.
Asunto(s)
Diterpenos/síntesis química , Diterpenos/farmacología , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/farmacología , Administración Oral , Animales , Bovinos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Corteza Cerebral/citología , Cristalografía por Rayos X , Diterpenos/administración & dosificación , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Sangre Fetal/química , Ácido Glutámico/toxicidad , Inyecciones Intravenosas , Modelos Moleculares , Conformación Molecular , Neuronas/citología , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/administración & dosificación , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Distribución TisularRESUMEN
Analogues of serofendic acid were prepared and their protective effects against L-glutamate (Glu)-induced neurotoxicity were examined using primary cultures of rat cortical neurons. Some analogues exhibited similar neuroprotective activity to that of serofendic acid.
Asunto(s)
Diterpenos/síntesis química , Diterpenos/farmacología , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/síntesis química , Síndromes de Neurotoxicidad/prevención & control , Animales , Células Cultivadas , Ácido Glutámico/efectos adversos , Síndromes de Neurotoxicidad/tratamiento farmacológico , Síndromes de Neurotoxicidad/patología , Ratas , Relación Estructura-ActividadRESUMEN
(-)-Methyl 7 beta-hydroxykaurenoate (3) and its 4-demethyl acetate (-)-4 were both synthesized via methods that contained radical cyclization and intramolecular Diels-Alder reactions as key steps. Both compounds displayed potent neuroprotective activity against N-methyl-D-aspartate toxicity in cultured cortical neurons.
Asunto(s)
Diterpenos/síntesis química , Fármacos Neuroprotectores/síntesis química , Animales , Células Cultivadas , Diterpenos/farmacología , Estructura Molecular , N-Metilaspartato/antagonistas & inhibidores , Fármacos Neuroprotectores/farmacologíaRESUMEN
We have previously reported that a novel neuroprotective substance named serofendic acid was purified and isolated from ether extract of fetal calf serum. In the present study, we investigated the effect of serofendic acid on acute neurotoxicity induced by L-glutamate (Glu) using primary cultures of rat cortical neurons. Exposure of cortical cultures to Glu for 1 h caused a marked decrease in cell viability, as determined by trypan blue exclusion. This acute Glu neurotoxicity was prevented by N-methyl-D-aspartate (NMDA) receptor antagonists, extracellular Ca(2+) removal, nitric oxide (NO) synthase inhibitor and NO scavenger. Serofendic acid prevented acute Glu neurotoxicity in a concentration-dependent manner. Acute neurotoxicity was induced by ionomycin, a Ca(2+) ionophore, and S-nitroso-L-cysteine, an NO donor. Serofendic acid also prevented both ionomycin- and S-nitroso-L-cysteine-induced neurotoxicity. Moreover, the protective effect of serofendic acid on acute Glu neurotoxicity was not affected by cycloheximide, a protein synthesis inhibitor, and actinomycin D, an RNA synthesis inhibitor. These results indicate that serofendic acid protects cultured cortical neurons from acute Glu neurotoxicity by reducing the cytotoxic action of NO and de novo protein synthesis is not required for this neuroprotection.
Asunto(s)
Células Cultivadas , Corteza Cerebral/citología , Cisteína/análogos & derivados , Diterpenos/uso terapéutico , Neuronas/patología , Síndromes de Neurotoxicidad/prevención & control , Glutamato de Sodio/efectos adversos , Valina/análogos & derivados , Animales , Calcio/antagonistas & inhibidores , Calcio/farmacología , Bovinos , Supervivencia Celular/efectos de los fármacos , Cisteína/efectos adversos , Cisteína/antagonistas & inhibidores , Cisteína/metabolismo , Diterpenos/aislamiento & purificación , Diterpenos/farmacología , Maleato de Dizocilpina/farmacología , Maleato de Dizocilpina/uso terapéutico , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Sangre Fetal/química , Feto/anatomía & histología , Ionomicina/efectos adversos , Ionomicina/antagonistas & inhibidores , Neuronas/citología , Neuronas/efectos de los fármacos , Óxido Nítrico/efectos adversos , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Quinoxalinas/farmacología , Quinoxalinas/uso terapéutico , Ratas , S-Nitrosotioles/efectos adversos , S-Nitrosotioles/antagonistas & inhibidores , S-Nitrosotioles/metabolismo , Glutamato de Sodio/antagonistas & inhibidores , Factores de Tiempo , Valina/farmacología , Valina/uso terapéuticoRESUMEN
A series of novel neuronal voltage-dependent calcium channel (VDCC) blockers, with inhibitory activity at low micromolar and moderate solubility in water, was discovered by constructing and screening a focused library based on emopamil (1) left hand (ELH) as a bioactive template.
Asunto(s)
Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo N/efectos de los fármacos , Sinaptosomas/efectos de los fármacos , Verapamilo/análogos & derivados , Verapamilo/química , Animales , Técnicas Químicas Combinatorias , Activación del Canal Iónico/efectos de los fármacos , Piperazinas/química , Ratas , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , Sinaptosomas/metabolismoRESUMEN
In the process of angiogenesis, endothelial adhesion molecules play a significant role in vascular morphogenesis, in coordination with angiogenic factor signaling. Here we report that a novel angiogenesis inhibitor, E7820 (an aromatic sulfonamide derivative), inhibited in vitro proliferation and tube formation of human umbilical vascular endothelial cell (HUVEC). E7820 decreased integrin alpha2, 3, 5, and beta1 in confluent culture of HUVEC, and integrin alpha2 was initially suppressed in mRNA level, followed by decrement of integrins alpha3, 5, and beta1. The inhibition of integrin alpha2 expression in HUVEC showed dose dependence but did not alter the level of CD31. Up-regulation of integrin alpha2 by phorbol 12-myristate 13-acetate abrogated the inhibitory effect of E7820 on tube formation within type I collagen gel, whereas addition of antibody against integrin alpha2 canceled the phorbol 12-myristate 13-acetate effect. These results suggest that E7820 inhibited tube formation through the suppression of integrin alpha2. Oral administration of E7820 remarkably resulted in inhibition of tumor-induced angiogenesis in mouse dorsal air sac model, and tumor growth of human colorectal tumor cell lines (WiDr and LoVo) was inhibited in xenotransplanted model in mice. This is the first time that a small molecule has been shown to modulate integrins, and this finding may provide the basis for a new approach to antiangiogenic therapy through the suppression of integrin alpha2 on endothelium.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Endotelio Vascular/efectos de los fármacos , Indoles/farmacología , Integrina alfa2/biosíntesis , Sulfonamidas/farmacología , Animales , División Celular/efectos de los fármacos , Neoplasias Colorrectales/irrigación sanguínea , Neoplasias Colorrectales/tratamiento farmacológico , Endotelio Vascular/citología , Endotelio Vascular/metabolismo , Femenino , Humanos , Ratones , Ratones Desnudos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
An asymmetric synthesis of (2S)-2-(2-isopropyl)-5-hydroxy-2-phenylpentanenitrile (emopamil left hand, 2) has been completed by use of the MAD (methyl aluminum bis(4-methyl-2,6-di-tert-butylphenoxide)-induced rearrangement of a chiral epoxyalcohol as the key reaction. The stereochemistry of the chiral quaternary center was confirmed by transformation of 2 to (S)-noremopamil. This method requires minimal purification procedures and affords high chemical and optical yields. Acid-catalyzed isomerization of an allylaldehyde and retro-aldol type racemization at the quaternary carbon of a nitrile-alcohol were encountered.
Asunto(s)
Verapamilo/análogos & derivados , Verapamilo/síntesis química , Catálisis , Química Orgánica/métodos , Cromatografía Líquida de Alta Presión , Espectroscopía de Resonancia Magnética , Estructura Molecular , Compuestos Organometálicos/química , Estereoisomerismo , Verapamilo/químicaRESUMEN
Excess activation of glutamate receptors and production of free radicals including nitric oxide may result in severe and irreversible damage to the mammalian central nervous system (CNS), but endogenous defense systems that protect neurons from these insults are poorly understood. Here, we purified and isolated a neuroprotective substance, which has been named "serofendic acid," from a lipophilic fraction of FCS based on the ability to protect rat primary cortical neurons against nitric oxide cytotoxicity. Mass spectrometry and NMR spectroscopy revealed the chemical structure of serofendic acid (15-hydroxy-17-methylsulfinylatisan-19-oic acid) as a sulfur-containing atisane-type diterpenoid, which is unique among known endogenous substances. Synthetic serofendic acid exhibited potent protective actions on cortical neurons against cytotoxicity of a nitric oxide donor as well as of glutamate, although it did not show appreciable influences on glutamate receptor-mediated responses in these neurons. Electron spin resonance analysis demonstrated that serofendic acid had no direct scavenging activity on nitric oxide radicals but was capable of inhibiting the generation of hydroxyl radical, a presumed "executor" radical in the nitric oxide-mediated neurotoxic cascade. These findings suggest that serofendic acid is a low-molecular-weight bioactive factor that promotes survival of CNS neurons, probably through the attenuation of free radical-mediated insults.