RESUMEN
Zika virus (ZIKV) is a member of the Flaviviridae family that can cause neurological disorders and congenital malformations. The NS2B-NS3 viral serine protease is an attractive target for the development of new antiviral agents against ZIKV. We report here a SAR study on a series of substrate-like linear tripeptides that inhibit in a non-covalent manner the NS2B-NS3 protease. Optimization of the residues at positions P1, P2, P3 and of the N-terminal and C-terminal portions of the tripeptide allowed the identification of inhibitors with sub-micromolar potency with phenylglycine as arginine-mimicking group and benzylamide as C-terminal fragment. Further SAR exploration and application of these structural changes to a series of peptides having a 4-substituted phenylglycine residue at the P1 position led to potent compounds showing double digit nanomolar inhibition of the Zika protease (IC50 = 30 nM) with high selectivity against trypsin-like proteases and the proteases of other flavivirus, such as Dengue 2 virus (DEN2V) and West Nile virus (WNV).
Asunto(s)
Antivirales/farmacología , Péptidos/farmacología , Inhibidores de Proteasas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Virus Zika/efectos de los fármacos , Antivirales/síntesis química , Antivirales/química , Virus del Dengue/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Péptidos/síntesis química , Péptidos/química , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/química , ARN Helicasas/antagonistas & inhibidores , ARN Helicasas/metabolismo , Serina Endopeptidasas/metabolismo , Relación Estructura-Actividad , Proteínas no Estructurales Virales/metabolismo , Virus del Nilo Occidental/efectos de los fármacos , Virus Zika/enzimologíaRESUMEN
Tourette syndrome (TS) and attention-deficit and hyperactivity disorder (ADHD) are co-morbid neurodevelopmental conditions affecting more commonly male patients. We set out to determine the impact of co-morbid ADHD on cognitive function in male children with TS by conducting a controlled study. Participants included four matched groups of unmedicated children (age range 6-15 years): TS (n=13), TS+ADHD (n=8), ADHD (n=39), healthy controls (n=66). Following clinical assessment, each participant completed a battery of tests from the Wechsler Intelligence Scale for Children-III, the Italian Battery for ADHD, the Tower of London test, the Corsi test, and the Digit Span test. All patient groups reported significantly lower scores than healthy controls across the neuropsychological tests involving executive functions. The TS+ADHD group was the most severely affected, followed by the ADHD group and the TS group, particularly in the tests assessing planning ability, inhibitory function, working memory and visual attention, but not auditory attention. Problems in executive functions are more common in patients with neurodevelopmental disorders than controls. Deficits in planning ability, inhibitory function, working memory and visual attention reported by children with TS appear to be more strongly related to the presence of co-morbid ADHD symptoms than core TS symptoms.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/psicología , Cognición , Pruebas Neuropsicológicas , Síndrome de Tourette/epidemiología , Síndrome de Tourette/psicología , Adolescente , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Niño , Cognición/fisiología , Comorbilidad , Función Ejecutiva/fisiología , Femenino , Humanos , Pruebas de Inteligencia/normas , Masculino , Memoria a Corto Plazo/fisiología , Pruebas Neuropsicológicas/normas , Síndrome de Tourette/diagnósticoRESUMEN
Histamine H(1) and serotonin 5-HT(2A) receptors mediate two different mechanisms involved in sleep regulation: H(1) antagonists are sleep inducers, while 5-HT(2A) antagonists are sleep maintainers. Starting from 9'a, a novel spirotetracyclic compound endowed with good H(1)/5-HT(2A) potency but poor selectivity, very high Cli, and a poor P450 profile, a specific optimization strategy was set up. In particular, we investigated the possibility of introducing appropriate amino acid moieties to optimize the developability profile of the series. Following this zwitterionic approach, we were able to identify several advanced leads (51, 65, and 73) with potent dual H(1)/5-HT(2A) activity and appropriate developability profiles. These compounds exhibited efficacy as hypnotic agents in a rat telemetric sleep model with minimal effective doses in the range 3-10 mg/kg po.
Asunto(s)
Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Antagonistas de los Receptores Histamínicos H1/síntesis química , Hipnóticos y Sedantes/síntesis química , Receptor de Serotonina 5-HT2A/metabolismo , Antagonistas del Receptor de Serotonina 5-HT2/síntesis química , Sueño/efectos de los fármacos , Compuestos de Espiro/síntesis química , Animales , Disponibilidad Biológica , Encéfalo/metabolismo , Línea Celular , Corteza Cerebral/metabolismo , Cricetinae , Cricetulus , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Antagonistas de los Receptores Histamínicos H1/química , Antagonistas de los Receptores Histamínicos H1/farmacología , Humanos , Hipnóticos y Sedantes/química , Hipnóticos y Sedantes/farmacología , Masculino , Microsomas Hepáticos/metabolismo , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Antagonistas del Receptor de Serotonina 5-HT2/química , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Trastornos del Sueño-Vigilia/tratamiento farmacológico , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A novel imidazobenzazepine template (5a) with potent dual H(1)/5-HT(2A) antagonist activity was identified. Application of a zwitterionic approach to this poorly selective and poorly developable starting point successfully delivered a class of high quality leads, 3-[4-(3-R(1)-2-R-5H-imidazo[1,2-b][2]benzazepin-11-yl)-1-piperazinyl]-2,2-dimethylpropanoic acids (e.g., 9, 19, 20, and 21), characterized by potent and balanced H(1)/5-HT(2A) receptor antagonist activities and good developability profiles.
Asunto(s)
Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Antagonistas de la Serotonina/uso terapéutico , Trastornos del Sueño-Vigilia/tratamiento farmacológico , HumanosAsunto(s)
Hidrazinas/química , Receptores de Ghrelina/antagonistas & inhibidores , Línea Celular , Evaluación Preclínica de Medicamentos , Trastornos de Alimentación y de la Ingestión de Alimentos/tratamiento farmacológico , Humanos , Hidrazinas/síntesis química , Hidrazinas/uso terapéutico , Receptores de Ghrelina/metabolismo , Relación Estructura-ActividadRESUMEN
Data from the Psychoeducational Profile-Revised (PEP-R) were analysed in a sample of 46 children, aged from 1.7 to 5.11 years, of whom 21 had autistic disorder (AD) and 25 had pervasive developmental disorder not otherwise specified (PDD-NOS). Analysis with a t-test for independent samples revealed a significant difference (p < 0.05) between children with AD and those with PDD-NOS on both developmental and behavioural PEP-R scales, supporting the utility of the PEP-R in discriminating between two diagnostic groups. This study emphasizes the effectiveness of the PEP-R as a tool for the early assessment of children with pervasive developmental disorders.
Asunto(s)
Trastorno Autístico/diagnóstico , Trastornos Generalizados del Desarrollo Infantil/diagnóstico , Pruebas Neuropsicológicas/estadística & datos numéricos , Trastorno Autístico/psicología , Trastornos de la Conducta Infantil/diagnóstico , Trastornos de la Conducta Infantil/psicología , Trastornos Generalizados del Desarrollo Infantil/psicología , Preescolar , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/psicología , Diagnóstico Diferencial , Femenino , Humanos , Lactante , Inteligencia , Trastornos del Desarrollo del Lenguaje/diagnóstico , Trastornos del Desarrollo del Lenguaje/psicología , Masculino , Psicometría/estadística & datos numéricos , Valores de Referencia , Reproducibilidad de los ResultadosRESUMEN
To identify new CRF(1) receptor antagonists, an attempt to modify the bis-heterocycle moiety present in the top region of the dihydropyrrole[2,3]pyridine template was made following new pharmacophoric hypothesis on the CRF(1) receptor antagonists binding pocket. In particular, the 2-thiazole ring, present in the previous series of compounds, was replaced by more hydrophilic non aromatic heterocycles able to make appropriate H-bond interactions with amino acid residues Thr192 and Tyr195. This exploration, followed by an accurate analysis of the substitution of the pendant aryl ring, enabled to identify in vitro potent compounds showing excellent pharmacokinetics and outstanding in vivo activity in animal models of anxiety, both in rodents and primates.
Asunto(s)
Piridinas/síntesis química , Piridinas/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Animales , Relación Dosis-Respuesta a Droga , Conducta Exploratoria/efectos de los fármacos , Femenino , Miembro Anterior/efectos de los fármacos , Gerbillinae , Humanos , Masculino , Modelos Químicos , Estructura Molecular , Actividad Motora/efectos de los fármacos , Pruebas Psicológicas , Piridinas/química , Pirroles/química , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Ultrasonido , Vocalización Animal/efectos de los fármacosAsunto(s)
Ansiedad/tratamiento farmacológico , Depresión/tratamiento farmacológico , Diseño de Fármacos , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Animales , Ansiedad/patología , Hormona Liberadora de Corticotropina/metabolismo , Depresión/patología , Modelos Químicos , Pirazoles/síntesis química , Pirazoles/farmacocinética , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
Corticotropin-releasing factor (CRF), a 41 amino acid peptide neurohormone synthesised by specific hypothalamic nuclei in the brain, is implicated in stress-related function. Antagonism of CRF(1) receptors is an attractive therapeutic approach for the treatment of depression and anxiety. Unsaturated tetrahydrotriazaacenaphthylenes of general structure 3 have been identified as potent and selective CRF(1) receptor antagonists with a suitable oral pharmacokinetic profile.
Asunto(s)
Naftalenos/farmacología , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Administración Oral , Humanos , Naftalenos/administración & dosificación , Naftalenos/química , Naftalenos/farmacocinética , Proteínas Recombinantes/antagonistas & inhibidoresRESUMEN
Two new classes of potent and selective CRF(1) receptor antagonists are presented. Exploration of general templates 3 and 4 through modifications of the top amine and bottom phenyl substituents led to optimization of the in vitro affinity and pharmacokinetic profiles. The typical alkyl chains present in the top region of CRF(1) antagonists were replaced by substituted heteroaryl moieties, leading to a dramatic improvement of the metabolic stability. This improvement was apparent when the compounds were dosed in vivo: several compounds exhibited low plasma clearance, good oral bioavailability, and high brain penetration. As a consequence of their outstanding pharmacokinetic profiles, these CRF(1) antagonists, as exemplified by compound 4 fi (4-(4-bromo-3-methyl-1H-pyrazol-1-yl)-7-(2,4-dichlorophenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine), produced a dose-dependent "anxiolytic-like" effect when administered orally, decreasing the vocalization of rat pups.
Asunto(s)
Pirimidinas/química , Pirimidinas/farmacología , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Animales , Ansiolíticos/química , Ansiolíticos/farmacología , Relación Dosis-Respuesta a Droga , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Estructura Molecular , Unión Proteica , Pirimidinas/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Vocalización Animal/efectos de los fármacosRESUMEN
The synthesis of a series of carbazole derivatives and their SAR at the NPY Y1 receptor is described. Modulation of physicochemical properties by appropriate decoration led to the identification of a high-affinity NPY Y1 antagonist that shows high brain penetration and modest oral bioavailability.