RESUMEN
We designed and synthesized a new biphenyl amide-tryptamine hybrid molecule 7 utilizing a pharmacophore-based approach as a 5-HT2B antagonist. The hybrid compound 7 was evaluated for its affinity to a panel of seven 5-HT receptors, demonstrating high selectivity for the 5-HT2B receptor. Functional assays revealed potent antagonism of 5-HT2B by 7 with an IC50 value of 14.1 nM. Moreover, compound 7 possessed a desirable in vitro pharmacokinetic profile and maintained its antagonistic potency in the presence of physiological concentrations of serum proteins. The design approach implemented in this investigation would facilitate the development of a second generation of highly selective and potent 5-HT2B antagonists.
RESUMEN
Multi-target-directed ligands (MTDLs) centered on ß-secretase 1 (BACE-1) inhibition are emerging as innovative therapeutics in addressing the complexity of neurodegenerative diseases. A new series of donepezil analogues was designed, synthesized and evaluated as MTDLs against neurodegenerative diseases. Profiling of donepezil, a potent acetylcholinesterase (hAChE) inhibitor, into BACE-1 inhibition was achieved through introduction of backbone amide linkers to the designed compounds which are capable of hydrogen-bonding with BACE-1 catalytic site. In vitro assays and molecular modeling studies revealed the dual mode of action of compounds 4-6 against hAChE and BACE-1. Notably, compound 4 displayed potent hAChE inhibition (IC50 value of 4.11â¯nM) and BACE-1 inhibition (IC50 value of 18.3â¯nM) in comparison to donepezil (IC50 values of 6.21 and 194â¯nM against hAChE and BACE-1, respectively). Moreover, 4 revealed potential metal chelating property, low toxicity on SH-SY5Y neuroblastoma cells and ability to cross the blood-brain barrier (BBB) in PAMPA-BBB assay which renders 4 a potential lead for further optimization of novel small ligands for the treatment of Alzheimer's disease.
Asunto(s)
Acetilcolinesterasa/química , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores de la Colinesterasa/síntesis química , Donepezilo/química , Diseño de Fármacos , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Sitios de Unión , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Dominio Catalítico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/uso terapéutico , Donepezilo/farmacología , Donepezilo/uso terapéutico , Humanos , Metales/química , Simulación de Dinámica Molecular , Permeabilidad/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
A new series of structurally rigid donepezil analogues was designed, synthesized and evaluated as potential multi-target-directed ligands (MTDLs) against neurodegenerative diseases. The investigated compounds 10-13 displayed dual AChE and BACE-1 inhibitory activities in comparison to donepezil, the FDA-approved drug. The hybrid compound 13 bearing 2-aminoquinoline scaffold exhibited potent AChE inhibition (IC50 value of 14.7â¯nM) and BACE-1 inhibition (IC50 value of 13.1â¯nM). Molecular modeling studies were employed to reveal potential dual binding mode of 13 to AChE and BACE-1. The effect of the investigated compounds on the viability of SH-SY5Y neuroblastoma cells and their ability to cross the blood-brain barrier (BBB) in PAMPA-BBB assay were further studied.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores de la Colinesterasa/farmacología , Donepezilo/farmacología , Diseño de Fármacos , Acetilcolinesterasa/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Barrera Hematoencefálica/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Cristalografía por Rayos X , Donepezilo/síntesis química , Donepezilo/química , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A new series of fluorene derivatives was designed and synthesized as novel retinoic acid receptor-related orphan receptor gamma t (RORγt) inverse agonists utilizing a molecular hybridization approach. The new compounds 10 - 15 were evaluated for their RORγt activity using biochemical FRET and cellular reporter gene assays. Moreover, the inhibitory activity of the fluorene derivatives 10 - 15 in mouse Th17 cell differentiation assay was assessed. The hybrid compound 15 that combines both fluorene and arylsulfone moieties displayed promising RORγt activity with IC50 values of 68.6 and 99.5 nm in FRET and cellular assays, respectively. In addition, molecular modeling studies were employed to investigate potential binding mode of 15 to RORγt. These results render 15 a potential lead compound for development of therapeutics for Th17-driven autoimmune diseases.
Asunto(s)
Agonismo Inverso de Drogas , Fluorenos/química , Fluorenos/farmacología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Animales , Barrera Hematoencefálica , Fluorenos/farmacocinética , Transferencia Resonante de Energía de Fluorescencia , Genes Reporteros , Ratones , Estructura Molecular , Relación Estructura-Actividad , Células Th17RESUMEN
OBJECTIVE: To evaluate the clinical efficacy of Verbena officinalis Linn decoction for patients with chronic generalized gingivitis in a double-blind randomized controlled multicenter clinical trial. METHOD AND MATERIALS: The patients in the test group and the control group were instructed to brush and floss. Additionally, the patients in the test group were asked to rinse their mouths with a V officinalis L decoction. The primary clinical outcome was the Gingival Index (GI). The GI and Plaque Index (PI) were measured at baseline (day 0), day 14, and day 28. RESULTS: Two hundred and sixty patients participated (control group = 130, and test group = 130). The clinical features of both the test and control groups were improved progressively throughout the time durations of day 0, day 14, and day 28 represented by highly significant decreases in both GI and PI (P < .001). The Mann-Whitney test revealed significant differences between the control and test groups for GI and PI at the 14-day examination and the 28-day examination (P < .001). At the beginning of the clinical trial, nonsignificant clinical differences were found following the statistical analyses of both GI (P = .981) and PI (P = .920) between the test and control groups. CONCLUSIONS: The tested V officinalis L decoction demonstrated efficacy in reducing tested indices and thus has a promising ameliorative effect for treating patients with chronic generalized gingivitis. CLINICAL SIGNIFICANCE: V officinalis L decoction has good clinical results with no adverse effects.