RESUMEN
α7 Nicotinic acetylcholine receptors (α7 nAChR) represent promising therapeutic candidates for the treatment of cognitive impairment associated with Alzheimer's disease (AD) and schizophrenia. A medicinal chemistry effort around previously reported compound 1 (SEN15924, WAY-361789) led to the identification of 12 (SEN78702, WYE-308775) a potent and selective full agonist of the α7 nAChR that demonstrated improved plasma stability, brain levels, and efficacy in behavioral cognition models.
Asunto(s)
Encéfalo/efectos de los fármacos , Cognición/efectos de los fármacos , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Agonistas Nicotínicos/farmacología , Piperidinas/farmacología , Pirazoles/farmacología , Receptores Nicotínicos/química , Animales , Células CHO , Calcio/metabolismo , Química Farmacéutica , Cricetinae , Canal de Potasio ERG1 , Humanos , Modelos Moleculares , Agonistas Nicotínicos/síntesis química , Piperidinas/síntesis química , Pirazoles/síntesis química , Ratas , Receptores Nicotínicos/metabolismo , Relación Estructura-Actividad , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
Alpha-7 nicotinic acetylcholine receptors (α7 nAChR) are implicated in the modulation of many cognitive functions such as attention, working memory, and episodic memory. For this reason, α7 nAChR agonists represent promising therapeutic candidates for the treatment of cognitive impairment associated with Alzheimer's disease (AD) and schizophrenia. A medicinal chemistry effort, around our previously reported chemical series, permitted the discovery of a novel class of α7 nAChR agonists with improved selectivity, in particular against the α3 receptor subtype and better ADME profile. The exploration of this series led to the identification of 5-(4-acetyl[1,4]diazepan-1-yl)pentanoic acid [5-(4-methoxyphenyl)-1H-pyrazol-3-yl] amide (25, SEN15924, WAY-361789), a novel, full agonist of the α7 nAChR that was evaluated in vitro and in vivo. Compound 25 proved to be potent and selective, and it demonstrated a fair pharmacokinetic profile accompanied by efficacy in rodent behavioral cognition models (novel object recognition and auditory sensory gating).
Asunto(s)
Azepinas/síntesis química , Agonistas Nicotínicos/síntesis química , Pirazoles/síntesis química , Receptores Nicotínicos/metabolismo , Administración Oral , Animales , Azepinas/farmacocinética , Azepinas/farmacología , Encéfalo/metabolismo , Calcio/metabolismo , Dominio Catalítico , Línea Celular , Permeabilidad de la Membrana Celular , Cognición/efectos de los fármacos , Perros , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Humanos , Masculino , Potenciales de la Membrana/efectos de los fármacos , Modelos Moleculares , Agonistas Nicotínicos/farmacocinética , Agonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/síntesis química , Antagonistas Nicotínicos/farmacocinética , Antagonistas Nicotínicos/farmacología , Técnicas de Placa-Clamp , Pirazoles/farmacocinética , Pirazoles/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Long-Evans , Reflejo de Sobresalto/efectos de los fármacos , Relación Estructura-Actividad , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
Alpha-7 nicotinic acetylcholine receptor (alpha7 nAChR) agonists are promising therapeutic candidates for the treatment of cognitive impairment. We report a series of novel, potent small molecule agonists (4-18) of the alpha7 nAChR deriving from our continuing efforts in the areas of Alzheimer's disease and schizophrenia. One of the compounds of the series containing a urea moiety (16) was further shown to be a selective agonist of the alpha7 nAChR with excellent in vitro and in vivo profiles, brain penetration, and oral bioavailability and demonstrated in vivo efficacy in multiple behavioral cognition models. Structural modifications leading to the improved selectivity profile and the biological evaluation of this series of compounds are discussed.
Asunto(s)
Agonistas Nicotínicos/síntesis química , Agonistas Nicotínicos/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Receptores Nicotínicos/metabolismo , Urea/análogos & derivados , Urea/síntesis química , Urea/farmacología , Administración Oral , Animales , Humanos , Concentración 50 Inhibidora , Masculino , Modelos Moleculares , Agonistas Nicotínicos/administración & dosificación , Agonistas Nicotínicos/farmacocinética , Conformación Proteica , Piridinas/administración & dosificación , Piridinas/farmacocinética , Ratas , Receptores Nicotínicos/química , Relación Estructura-Actividad , Especificidad por Sustrato , Urea/administración & dosificación , Urea/farmacocinética , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
Sodium (Na) channels continue to represent an important target for the development of novel anticonvulsants. We have synthesized and evaluated a series of 2,4(5)-diarylimidazoles for inhibition of the human neuronal Na(V)1.2 Na channel isoform. Starting with the unsubstituted lead compound previously published 3, SAR studies were performed introducing substituents with different physico-chemical properties. Lipophilicity (log D(7.4)) and basicity (pK(a)) of the compounds were measured and submitted for QSPR investigations. Some of the active compounds described had IC(50) values that were considerably lower than our lead compound. In particular, the m-CF(3) disubstituted 22 was the most active compound, inhibiting hNa(V)1.2 currents within the nanomolar concentration range (IC(50)=200 nM). In comparison, lamotrigine and phenytoin, two clinically used anticonvulsant drugs known to inhibit Na channels, had IC(50)'s values that were greater than 100 microM.
Asunto(s)
Imidazoles/farmacología , Bloqueadores de los Canales de Sodio/farmacología , Canales de Sodio/metabolismo , Línea Celular , Electrofisiología , Humanos , Imidazoles/síntesis química , Imidazoles/química , Concentración 50 Inhibidora , Bloqueadores de los Canales de Sodio/síntesis química , Bloqueadores de los Canales de Sodio/química , Canales de Sodio/química , Relación Estructura-ActividadRESUMEN
A small family of novel 2,4(5)-diarylimidazoles were prepared through a simple and efficient synthesis and evaluated as potential inhibitors of hNa(v)1.2 sodium channel currents. One member of this series (4) exhibited profound inhibition of Na(v)1.2 currents, emerging as a promising lead compound for further structure-activity relationship studies for the development of novel sodium channel blockers.
Asunto(s)
Química Farmacéutica/métodos , Imidazoles/síntesis química , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/química , Bloqueadores de los Canales de Sodio/síntesis química , Canales de Sodio/química , Diseño de Fármacos , Humanos , Imidazoles/farmacología , Activación del Canal Iónico , Modelos Químicos , Estructura Molecular , Canal de Sodio Activado por Voltaje NAV1.2 , Isoformas de Proteínas , Sodio/química , Bloqueadores de los Canales de Sodio/química , Bloqueadores de los Canales de Sodio/farmacología , Relación Estructura-ActividadRESUMEN
A parallel synthesis of aryl azoles with neuroprotective activity is described. All compounds obtained were evaluated in an in vitro assay using a NMDA toxicity paradigm showing a neuroprotective activity between 15% and 40%. The potential biological target of the active compounds was investigated by extensive literature searches based around similar scaffolds with reported neuroprotective activity. The most interesting molecules active in the NMDA toxicity assay (3a and 2g) showed moderate but significant activity in the inhibition of the Site 2 Sodium Channel binding assay at 10 microM. To confirm our hypothesis compounds 3a, c, f and 2g were tested in the Veratridine assay which is one of the excitotoxicity assays of relevance to NaV channels. The compounds tested showed an activity between 40% and 70%. The identification of neuroprotective small molecules and the identification of NaV channels as the potential site of action were the most important goals of this work.
Asunto(s)
Azoles/farmacología , Fármacos Neuroprotectores/síntesis química , Animales , Azoles/síntesis química , Humanos , N-Metilaspartato/toxicidad , Fármacos Neuroprotectores/farmacología , Bloqueadores de los Canales de Sodio/síntesis química , Bloqueadores de los Canales de Sodio/farmacología , Canales de Sodio/efectos de los fármacosRESUMEN
A simple and efficient approach to selectively obtain 2,4(5)-diarylimidazoles suppressing formation of 2-aroyl-4(5)-arylimidazoles is described. The yield of each of the two products strongly depends on the reaction conditions employed. This reaction provides a simple method to prepare small libraries of biologically active compounds by parallel synthesis.
Asunto(s)
Derivados del Benceno/síntesis química , Imidazoles/síntesis químicaRESUMEN
A novel series of non-imidazole H(3)-receptor antagonists was developed, by chemical modification of a potent lead H(3)-antagonist composed by an imidazole ring connected through an alkyl spacer to a 2-aminobenzimidazole moiety (e.g., 2-[[3-[4(5)-imidazolyl]propyl]amino]benzimidazole), previously reported by our research group. We investigated whether the removal of the imidazole ring could allow retaining high affinity for the H(3)-receptor, thanks to the interactions undertaken by the 2-aminobenzimidazole moiety at the binding site. The imidazole ring of the lead was replaced by a basic piperidine or by a lipophilic p-chlorophenoxy substituent, modulating the spacer length from three to eight methylene groups; moreover, the substituents were moved to the 5(6) position of the benzimidazole nucleus. Within both the 2-alkylaminobenzimidazole series and the 5(6)-alkoxy-2-aminobenzimidazole one, the greatest H(3)-receptor affinity was obtained for the piperidine-substituted compounds, while the presence of the p-chlorophenoxy group resulted in a drop in affinity. The optimal chain length was different in the two series. Even if the new compounds did not reach the high receptor affinity shown by the imidazole-containing lead compound, it was possible to get good H(3)-antagonist potencies with 2-aminobenzimidazoles having a tertiary amino group at appropriate distance.