RESUMEN
We synthesized several biaryl derivatives as PDE10A inhibitors to prevent phototoxicity of 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (1) and found that the energy difference between the energy-minimized conformation and the coplanar conformation of the biaryl moiety helped facilitate prediction of the phototoxic potential of biaryl compounds. Replacement of the quinoline ring of 1 with N-methyl benzimidazole increased this energy difference and prevented phototoxicity in the 3T3 NRU test. Further optimization identified 1-methyl-5-(1-methyl-3-{[4-(1-methyl-1H-benzimidazol-4-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridin-2(1H)-one (38b). Compound 38b exhibited good selectivity against other PDEs, and oral administration of 38b improved visual-recognition memory deficit in mice at doses of 0.001 and 0.003mg/kg in the novel object recognition test. ASP9436 (sesquiphosphate of 38b) may therefore be used for the treatment of schizophrenia with a low risk of phototoxicity.
Asunto(s)
Antipsicóticos/química , Bencimidazoles/química , Inhibidores de Fosfodiesterasa/química , Hidrolasas Diéster Fosfóricas/metabolismo , Piridinas/química , Quinolinas/química , Esquizofrenia/tratamiento farmacológico , Administración Oral , Animales , Antipsicóticos/administración & dosificación , Antipsicóticos/efectos adversos , Conducta Animal/efectos de los fármacos , Bencimidazoles/administración & dosificación , Bencimidazoles/efectos adversos , Sitios de Unión , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Alucinógenos , Humanos , Masculino , Ratones , Ratones Endogámicos ICR , Reconocimiento Visual de Modelos/efectos de los fármacos , Fenciclidina , Inhibidores de Fosfodiesterasa/administración & dosificación , Inhibidores de Fosfodiesterasa/efectos adversos , Hidrolasas Diéster Fosfóricas/química , Procesos Fotoquímicos , Unión Proteica , Piridinas/administración & dosificación , Piridinas/efectos adversos , Quinolinas/administración & dosificación , Quinolinas/efectos adversos , Esquizofrenia/inducido químicamente , Esquizofrenia/enzimología , Esquizofrenia/fisiopatología , Rayos UltravioletaRESUMEN
Oxidative stress is widely recognized as being associated with a number of disorders, including metabolic dysfunction and atherosclerosis. A series of substituted 4-quinolone derivatives were prepared and evaluated as inhibitors of reactive oxygen species (ROS) production from human umbilical vein endothelial cells (HUVECs). One compound in particular, 2-({[4-(3-hydroxy-3-methylbutoxy)pyridin-2-yl]oxy}methyl)-3-methylquinolin-4(1H)-one (25b), inhibited ROS production from HUVECs with an IC(50) of 140 nM. This compound also exhibited low CYP2D6 inhibitory activity, high aqueous solubility, and good in vitro metabolic stability. An in vivo pharmacokinetic study of this compound in SD rats revealed high oral bioavailability and a long plasma half-life.
Asunto(s)
4-Quinolonas/química , 4-Quinolonas/farmacología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , 4-Quinolonas/farmacocinética , Animales , Citocromo P-450 CYP2D6/metabolismo , Inhibidores del Citocromo P-450 CYP2D6 , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Ratas , Ratas Sprague-DawleyRESUMEN
Although exogenous agonists for cannabinoid (CB) receptors are clinically effective for treating chronic pain, global activation of brain CB receptors causes frequent central nervous system (CNS) side-effects. Fatty acid amide hydrolase (FAAH) is a primary catabolic enzyme for anandamide (AEA), an endogenous CB. Recently, we discovered a novel FAAH inhibitor, 3-pyridyl 4-(phenylcarbamoyl)piperidine-1-carboxylate (ASP8477). In vitro studies demonstrated that ASP8477 inhibited human FAAH-1, FAAH-1 (P129T) and FAAH-2 activity with IC50 values of 3.99, 1.65 and 57.3nM, respectively. ASP8477 at 10µM had no appreciable interactions with 65 different kinds of receptors, ion channels, transporters and enzymes, including CB1 and CB2 receptors and monoacylglycerol lipase. In adolescent rats, orally administered ASP8477 (0.3-10mg/kg) elevated AEA concentrations in both plasma and brain. In a capsaicin-induced secondary hyperalgesia model, a pretreatment with ASP8477 significantly improved mechanical allodynia and thermal hyperalgesia at 0.3-3mg/kg p.o. ASP8477 also significantly improved mechanical allodynia in an L5/L6 spinal nerve ligation neuropathic pain model, with an ED50 value of 0.63mg/kg, and in a streptozotocin-induced diabetic neuropathy model at 3 and 10mg/kg p.o. Furthermore, ASP8477 significantly attenuated the reduction in rearing events at 1 and 3mg/kg p.o. in a monoiodoacetic acid-induced osteoarthritis model. Importantly, ASP8477 had no significant effect on motor coordination up to 30mg/kg p.o. These results indicate that ASP8477 is a potent, selective, and oral active FAAH inhibitor with activity in the CNS, with the potential to be a new analgesic agent with a wide safety margin.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Ácidos Carboxílicos/farmacología , Inhibidores Enzimáticos/farmacología , Administración Oral , Analgésicos/administración & dosificación , Analgésicos/farmacología , Animales , Ácidos Araquidónicos/metabolismo , Ácidos Carboxílicos/administración & dosificación , Relación Dosis-Respuesta a Droga , Endocannabinoides/metabolismo , Inhibidores Enzimáticos/administración & dosificación , Humanos , Masculino , Alcamidas Poliinsaturadas/metabolismo , Desempeño Psicomotor/efectos de los fármacos , RatasRESUMEN
The proline-rich motif in proteins is known to function as a ligand sequence that binds to protein modules such as SH3, WW, and several other protein interaction domains. These proline-rich ligand-mediated protein-protein interactions (abbreviated PLPI) are important in many signaling pathways that are involved in various diseases. Our previous studies showed that UCS15A, produced by Streptomyces species, inhibited PLPI. Here we report on synthetic analogs of UCS15A that show more potent activity than UCS15A in inhibiting PLPI. A synthetic analog, compound 2c, blocked in vitro PLPI of Sam68-Fyn-SH3 as well as in vivo PLPI of Grb2-Sam68 and Grb2-Sos1. Activation of MEK was also inhibited by compound 2c. Unlike UCS15A, compound 2c was an order of magnitude less cytotoxic and did not cause morphological changes in treated cells.