RESUMEN
BACKGROUND: Hazelnut oral immunotherapy (H-OIT), a promising alternative to hazelnut-free diet for patients with hazelnut allergy, has not been extensively studied. OBJECTIVE: To investigate the effectiveness of H-OIT for children with hazelnut allergy. METHODS: Retrospective medical record review of children treated by H-OIT in the University Hospital of Lyon (France) was reported. Clinical and laboratory data were collected, and the satisfaction of the children treated by H-OIT was evaluated using a questionnaire. RESULTS: A total of 70 patients treated by H-OIT for an immunoglobulin E-mediated hazelnut allergy (94.3%) or an immunoglobulin E sensitization to hazelnut (5.7%) were included. Among these, 22.9% entered the maintenance phase at 1-year consultation and 60.0% entered the maintenance phase during the study period. At home, 57.1% of the patients experienced at least 1 adverse effect and 2.9% experienced severe systemic allergic reactions. Among the 212 oral food challenges conducted at hospital, 3.3% led to severe systemic reactions and epinephrine was used 4 times. A total of 21.4% of children discontinued treatment; aversion to hazelnut was the main reason. There were 42 children aged 8 years or more and their parents who answered the questionnaire. H-OIT was considered a strain for children but effective and was recommended to other children with allergy. CONCLUSION: H-OIT seemed to be effective and well accepted by children. This is counterbalanced by a high rate of H-OIT discontinuation, mainly owing to aversion to hazelnut, and an important rate of adverse reactions, which are however mostly mild. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04841850.
Asunto(s)
Corylus , Hipersensibilidad al Cacahuete , Administración Oral , Alérgenos , Niño , Desensibilización Inmunológica/efectos adversos , Humanos , Inmunoterapia , Estudios RetrospectivosRESUMEN
The optimization of a potent and highly selective series of dual mTORC1 and mTORC2 inhibitors is described. An initial focus on improving cellular potency whilst maintaining or improving other key parameters, such as aqueous solubility and margins over hERG IC(50), led to the discovery of the clinical candidate AZD8055 (14). Further optimization, particularly aimed at reducing the rate of metabolism in human hepatocyte incubations, resulted in the discovery of the clinical candidate AZD2014 (21).
Asunto(s)
Morfolinas/farmacología , Complejos Multiproteicos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Benzamidas , Procesos de Crecimiento Celular/efectos de los fármacos , Células Cultivadas , Hepatocitos/efectos de los fármacos , Hepatocitos/enzimología , Hepatocitos/metabolismo , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina , Diana Mecanicista del Complejo 2 de la Rapamicina , PirimidinasRESUMEN
A pharmacophore mapping approach, derived from previous experience of PIKK family enzymes, was used to identify a hit series of selective inhibitors of the mammalian target of rapamycin (mTOR). Subsequent refinement of the SAR around this hit series based on a tri-substituted triazine scaffold has led to the discovery of potent and selective inhibitors of mTOR.
Asunto(s)
Antineoplásicos/química , Morfolinas/química , Inhibidores de Proteínas Quinasas/química , Proteínas Quinasas/química , Pirimidinas/química , Triazinas/química , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Línea Celular Tumoral , Humanos , Morfolinas/síntesis química , Morfolinas/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Pirimidinas/síntesis química , Pirimidinas/farmacología , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR , Triazinas/síntesis química , Triazinas/farmacologíaRESUMEN
We describe a novel series of potent inhibitors of the kinase activity of mTOR. The compounds display good selectivity relative to other PI3K-related kinase family members and, in cellular assays, inhibit both mTORC1 and mTORC2 complexes and exhibit good antiproliferative activity.
Asunto(s)
Antineoplásicos/química , Diaminas/química , Morfolinas/química , Inhibidores de Proteínas Quinasas/química , Proteínas Quinasas/química , Pirimidinas/química , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Línea Celular , Diaminas/síntesis química , Diaminas/farmacología , Descubrimiento de Drogas , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina , Morfolinas/síntesis química , Morfolinas/farmacología , Complejos Multiproteicos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Proteínas , Pirimidinas/síntesis química , Pirimidinas/farmacología , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismoRESUMEN
Poly(ADP-ribose) polymerase activation is an immediate cellular response to metabolic-, chemical-, or ionizing radiation-induced DNA damage and represents a new target for cancer therapy. In this article, we disclose a novel series of substituted 4-benzyl-2 H-phthalazin-1-ones that possess high inhibitory enzyme and cellular potency for both PARP-1 and PARP-2. Optimized compounds from the series also demonstrate good pharmacokinetic profiles, oral bioavailability, and activity in vivo in an SW620 colorectal cancer xenograft model. 4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2 H-phthalazin-1-one (KU-0059436, AZD2281) 47 is a single digit nanomolar inhibitor of both PARP-1 and PARP-2 that shows standalone activity against BRCA1-deficient breast cancer cell lines. Compound 47 is currently undergoing clinical development for the treatment of BRCA1- and BRCA2-defective cancers.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Ftalazinas/síntesis química , Ftalazinas/farmacología , Piperazinas/síntesis química , Piperazinas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Perros , Inhibidores Enzimáticos/química , Humanos , Ratones , Estructura Molecular , Ftalazinas/química , Piperazinas/química , Poli(ADP-Ribosa) Polimerasas/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
We have previously described poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors based on a substituted benzyl-phthalazinone scaffold. As an alternative chemical template, a novel series of alkoxybenzamides were developed with restricted conformation through intramolecular hydrogen bond formation; the compounds exhibit low nM enzyme and cellular activity as PARP-1 inhibitors.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Química Farmacéutica , Diseño de Fármacos , Inhibidores Enzimáticos/química , Células HeLa , Humanos , Enlace de Hidrógeno , Concentración 50 Inhibidora , Modelos Químicos , Conformación Molecular , Estructura Molecular , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas/química , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
Inhibitors of PDE5 are useful therapeutic agents for treatment of erectile dysfunction. A series of novel xanthine derivatives has been identified as potent inhibitors of PDE5, with good levels of selectivity against other PDE isoforms, including PDE6. Studies in the dog indicate excellent oral bioavailability for compound 21.
Asunto(s)
3',5'-GMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Xantinas/farmacología , Animales , Disponibilidad Biológica , Bovinos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , Perros , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Disfunción Eréctil/tratamiento farmacológico , Humanos , Concentración 50 Inhibidora , Masculino , Farmacocinética , Isoformas de Proteínas/efectos de los fármacos , Relación Estructura-Actividad , Xantinas/químicaRESUMEN
Screening of the Maybridge compound collection identified 4-arylphthalazinones as micromolar inhibitors of PARP-1 catalytic activity. Subsequent optimisation of both inhibitory activity and metabolic stability led to a novel series of meta-substituted 4-benzyl-2H-phthalazin-1-ones with low nanomolar, cellular activity as PARP-1 inhibitors and promising metabolic stability in vitro.
Asunto(s)
Ftalazinas/síntesis química , Ftalazinas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Imidas/síntesis química , Imidas/química , Imidas/farmacología , Cinética , Modelos Moleculares , Estructura Molecular , Ftalazinas/química , Poli(ADP-Ribosa) Polimerasa-1 , Relación Estructura-ActividadRESUMEN
In clinical studies, several inhibitors of phosphodiesterase 5 (PDE5) have demonstrated utility in the treatment of erectile dysfunction. We describe herein a series of 8-aryl xanthine derivatives which function as potent PDE5 inhibitors with, in many cases, high levels of selectivity versus other PDE isoforms.