RESUMEN
Glomeruli and renal tubule injury in chronic kidney disease (CKD) is reported to involve induction of macrophage activation through the CCL2/CCR2 axis. The effects of inhibitors of the CCL2/CCR2 axis, such as anti-CCL2 antibody and CCR2 antagonist, on kidney function in animal models or humans with kidney dysfunction have been demonstrated. The N-terminal glutamine on immature CCL2 is replaced with pyroglutamate (pE) by glutaminyl cyclase (QC) and isoQC. pE-CCL2 is stable and resistant to peptidases. We hypothesized that inhibiting QC/isoQC activity would lead to the degradation of CCL2, thereby ameliorating CKD and reducing kidney inflammation. To test this hypothesis, we investigated the renoprotective properties of the QC/isoQC inhibitor PQ529 in anti-glomerular basement membrane (GBM) antibody-induced glomerulonephritis Wistar Kyoto (WKY) rats. Three-week repeated administration of PQ529 (30 and 100 mg/kg, twice daily) significantly reduced the serum and urine CCL2 and urinary protein excretion in a dose-dependent manner. Correlations between the urinary protein level and serum or urinary CCL2 levels were confirmed in tested animals. Repeated administration of PQ529 significantly reduced the expression of CD68, a macrophage marker, in the kidney cortex and mononuclear infiltration into the tubulointerstitium. In addition, decreased levels of urinary KIM-1, ß2 microglobulin, and clusterin were detected, suggesting the inhibition of inflammation in both the proximal and distal tubules. These results suggest that PQ529 suppresses the progression of inflammation-induced renal dysfunction by inhibiting the CCL2/CCR2 axis. Inhibition of QC/isoQC may thus be a viable alternative therapeutic approach for treating glomerulonephritis and CKD patients.
Asunto(s)
Aminoaciltransferasas/antagonistas & inhibidores , Bencimidazoles/uso terapéutico , Glomerulonefritis/tratamiento farmacológico , Imidazolinas/uso terapéutico , Sustancias Protectoras/uso terapéutico , Insuficiencia Renal Crónica/tratamiento farmacológico , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/genética , Antígenos de Diferenciación Mielomonocítica/metabolismo , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Moléculas de Adhesión Celular/orina , Quimiocina CCL2/antagonistas & inhibidores , Quimiocina CCL2/sangre , Quimiocina CCL2/metabolismo , Quimiocina CCL2/orina , Clusterina/orina , Glomerulonefritis/sangre , Glomerulonefritis/metabolismo , Glomerulonefritis/orina , Imidazolinas/farmacocinética , Imidazolinas/farmacología , Interferón gamma/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Masculino , Sustancias Protectoras/farmacocinética , Sustancias Protectoras/farmacología , Ratas Endogámicas WKY , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/orina , Microglobulina beta-2/orinaRESUMEN
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
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
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
A series of novel indazole derivatives were synthesized, and their structure-activity relationships examined in order to identify potent and selective 5-HT2C receptor agonists. Among these compounds, (S)-2-(7-ethyl-1H-furo[2,3-g]indazol-1-yl)-1-methylethylamine (YM348) had a good in vitro profile, that is, high agonistic activity to the human 5-HT2C receptor subtype (EC50 = 1.0 nM) and high selectivity over 5-HT2A receptors. This compound was also effective in a rat penile erection model when administered p.o.
Asunto(s)
Indazoles/farmacología , Agonistas del Receptor de Serotonina 5-HT2 , Agonistas de Receptores de Serotonina/síntesis química , Animales , Etilaminas/síntesis química , Etilaminas/farmacología , Humanos , Indazoles/síntesis química , Erección Peniana/efectos de los fármacos , Ratas , Agonistas de Receptores de Serotonina/farmacología , Relación Estructura-ActividadRESUMEN
To identify potent and selective 5-HT(2C) receptor agonists, a series of novel benzazepine derivatives were synthesized, and their structure-activity relationships examined. The compounds were evaluated for their 5-HT(2C), 5-HT(2A), and 5-HT(2B) receptor binding affinity and intrinsic activity for the 5-HT(2C) and 5-HT(2A) receptors. Among these compounds, 6,7-dichloro-2,3,4,5-tetrahydro-1H-3-benzazepine (6) was effective in a rat penile erection model when administered po, which is a symptom of the serotonin syndrome reflecting 5-HT(2C) receptor activation. Moreover, compound 6 was characterized as a partial agonist of 5-HT(2A) receptors; therefore, it had little effect on the cardiovascular system.
Asunto(s)
Benzazepinas/química , Benzazepinas/farmacología , Agonistas del Receptor de Serotonina 5-HT2 , Animales , Benzazepinas/síntesis química , Sistema Cardiovascular/efectos de los fármacos , Erección Peniana/efectos de los fármacos , Ratas , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Receptor de Serotonina 5-HT2B/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
YM348, (S)-2-(7-ethyl-1H-furo[2,3-g]indazol-1-yl)-1-methylethylamine, showed a high affinity for cloned human 5-HT(2C) receptors (K(i): 0.89 nM). The functional selectivity for 5-HT(2C) receptors in the 5-HT(2) receptor family was the highest among 5-HT(2C) receptor agonists, including m-chlorophenylpiperazine (mCPP) and Ro60-0175 ((S)-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine). Oral administration of YM348 induced penile erections and hypolocomotion in rats, being completely inhibited by a selective 5-HT(2C) receptor antagonist, SB242084 (6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy) pyridin-3-yl carbamoyl] indoline). The dose-response curve for penile erections, unlike that for hypolocomotion, was an inverted U-shape in the dose range of 0.0677-2.03 mg/kg. A selective 5-HT(2A) receptor antagonist, MDL100907 (R(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol), and a selective 5-HT(2B) receptor antagonist, RS-127445 (2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine), had no effect on the decline in penile erection frequency at 2.03 mg/kg of YM348. YM348 did not affect blood pressure at 2.03 mg/kg. In conclusion, YM348 is a novel, potent and orally active 5-HT(2C) receptor agonist, and neither the activation of 5-HT(2A) or 5-HT(2B) receptors nor a cardiovascular effect is likely to contribute to the inverted U-shape dose-response curve for penile erections.