RESUMEN
To identify novel glycine transporter 1(GlyT1) inhibitors with greater selectivity relative to GlyT2 and improved aqueous solubility, we synthesized a series of 4H-1,2,4-triazole derivatives with heteroaromatic rings at the 4-position and investigated their structure-activity relationships. Replacement of the 2-fluorophenyl group of lead compound 5 with various aromatic groups led to the identification of 5-(3-biphenyl-4-yl-5-ethyl-4H-1,2,4-triazol-4-yl)isoquinoline (15) with 38-fold selectivity between GlyT1 and GlyT2. 15 also showed improved aqueous solubility and in vivo efficacy on (+)-HA966-induced hyperlocomotion in mice over the lead compound.
Asunto(s)
Compuestos de Bifenilo/síntesis química , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Isoquinolinas/química , Isoquinolinas/síntesis química , Triazoles/química , Animales , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Línea Celular , Proteínas de Transporte de Glicina en la Membrana Plasmática/metabolismo , Isoquinolinas/farmacología , Masculino , Ratones , Ratones Endogámicos ICR , Actividad Motora/efectos de los fármacos , Ratas , Solubilidad , Relación Estructura-ActividadRESUMEN
A series of 5-(4-biphenyl)-3-methyl-4-phenyl-1,2,4-triazole derivatives were prepared and evaluated as selective antagonists for the human vasopressin V(1A) receptor. The compounds were examined for their affinity to the cloned human V(1A) receptor (hV(1A)) and selectivity vs the cloned human V(2) receptor (hV(2)). By utilizing the structure-activity relationship on 4,4-difluoro-5-methylidene-2,3,4,5-tetrahydrobenzazepine derivatives as dual antagonists for the V(1A) and V(2) receptors in our previous study, we found that substituting the methoxy group at the 2-position of the 4-phenyl ring with (4-methylpiperazin-1-yl)alkoxy moieties brought about marked improvement of both affinity to hV(1A) and selectivity vs hV(2). Further introduction of a methyl group into the 6-position of the 4-phenyl ring resulted in additional improvement of selectivity. One particular compound, 5-(4-biphenyl)-3-methyl-4-[2-[6-(4-methyl-1-piperazinyl)hexyloxy]phenyl]-1,2,4-triazole (19) showed potent affinity to hV(1A) with a K(i) value of 1.04 nM and high selectivity with a 1700-fold selectivity vs hV(2). We also found marked differences in the affinity of compounds in this series between the human and the rat receptors. Compound 19 was further examined for its V(1A) receptor antagonist activity in rats. As a result, 19 demonstrated antagonist activities toward an arginine vasopressin-induced increase in diastolic blood pressure after intravenous or oral administration and long-lasting oral activity.
Asunto(s)
Antagonistas de los Receptores de Hormonas Antidiuréticas , Piperazinas/síntesis química , Triazoles/síntesis química , Administración Oral , Animales , Antihipertensivos/síntesis química , Antihipertensivos/química , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Células CHO , Clonación Molecular , Cricetinae , Humanos , Inyecciones Intravenosas , Riñón/metabolismo , Hígado/metabolismo , Masculino , Piperazinas/química , Piperazinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Receptores de Vasopresinas/metabolismo , Especificidad de la Especie , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacologíaRESUMEN
We report on the optimization of 4H-1,2,4-triazole derivatives to increase their activity and selectivity as glycine transporter 1 (GlyT1) inhibitors. Structure-activity relationship exploration resulted in the identification of a 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzonitrile (14u) compound with markedly higher selectivity for GlyT1. Physiochemical studies revealed that 14u exists as a stable pair of atropisomers under physiological conditions. We successfully separated the atropisomers to obtain active enantiomer (R)-14u, which displayed favorable pharmacokinetic properties, as well as positive results in the mice Y-maze test.
Asunto(s)
Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Triazoles/síntesis química , Animales , Maleato de Dizocilpina/farmacología , Femenino , Humanos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos ICR , Ratas , Ratas Wistar , Relación Estructura-Actividad , Triazoles/farmacologíaRESUMEN
We describe the preparation and evaluation of a novel series of glycine transporter 1 (GlyT1) inhibitors derived from a high-throughput screening hit. The SAR studies resulted in the discovery of 3-biphenyl-4-yl-4-(2-fluorophenyl)-5-isopropyl-4H-1,2,4-triazole (6p). A pharmacokinetic study was also conducted and revealed that 6p had excellent oral bioavailability and ameliorated learning impairment in passive avoidance tasks in mice.
Asunto(s)
Compuestos de Bifenilo/síntesis química , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Nootrópicos/síntesis química , Triazoles/síntesis química , Animales , Reacción de Prevención/efectos de los fármacos , Disponibilidad Biológica , Compuestos de Bifenilo/farmacocinética , Compuestos de Bifenilo/farmacología , Encéfalo/metabolismo , Permeabilidad de la Membrana Celular , Ratones , Actividad Motora/efectos de los fármacos , Nootrópicos/farmacocinética , Nootrópicos/farmacología , Relación Estructura-Actividad , Triazoles/farmacocinética , Triazoles/farmacologíaRESUMEN
To find potent and selective antagonists of the arginine vasopressin (AVP) V1A receptor, optimization studies of compounds structurally related to (Z)-N-{4'-[(4,4-difluoro-5-carbamoylmethylidene-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]phenyl}carboxamide were performed. The synthesis and pharmacological properties of these compounds are described. We first investigated the effect of the carboxamide moiety, and found that a 2-methylfuran-3-carbonyl group at this position increased V1A binding affinity and selectivity for the V1A receptor versus the V2 receptor. The amino group of the 5-carbamoylmethylidene moiety was also examined, and a 4-piperidinopiperidino group was found to be optimal at this position. The hemifumarate of compound 12l (YM218) was shown to exhibit potent binding affinity, V1A receptor selectivity, and in vivo antagonist activity.
Asunto(s)
Antagonistas de los Receptores de Hormonas Antidiuréticas , Benzazepinas/química , Benzazepinas/farmacología , Flúor/química , Animales , Benzazepinas/síntesis química , Células Cultivadas , Evaluación Preclínica de Medicamentos , Flúor/farmacología , Humanos , Masculino , Estructura Molecular , Péptidos/química , Péptidos/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
In the search for a novel class of selective antagonists for the human V(1A) receptor, high-throughput screening (HTS) of the Yamanouchi chemical library using CHO cells expressing the cloned human V(1A) (hV(1A)) receptor led to the discovery of 5-(4-biphenyl)-4-(2-methoxyphenyl)-3-methyl-1,2,4-triazole (3) which possessed the novel 4,5-diphenyl-1,2,4-triazole structure. Subsequent structure-activity relationships studies on a series of the 4,5-diphenyl-1,2,4-triazole derivatives related to 3 revealed that the 4,5-diphenyl-1,2,4-triazole structure played an essential role in exerting high affinity for the hV(1A) receptor and that introduction of a basic amine moiety to the methoxy part of the 4-phenyl ring was effective in the improvement of both affinity for the hV(1A) receptor and selectivity versus the hV(2) receptor. Compound 3 and the 2-(morphorino)ethoxy derivative (11b) were shown to be antagonists for the hV(1A) receptor, from their effects on AVP-induced [Ca(2+)](i) response in CHO cells expressing the hV(1A) receptor.