RESUMEN
Tpl2 (cot/MAP3K8) is an upstream kinase of MEK in the ERK pathway. It plays an important role in Tumor Necrosis Factor-alpha (TNF-alpha) production and signaling. We have discovered that 8-halo-4-(3-chloro-4-fluoro-phenylamino)-6-[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-quinoline-3-carbonitriles (4) are potent inhibitors of this enzyme. In order to improve the inhibition of TNF-alpha production in LPS-stimulated human blood, a series of analogs with a variety of substitutions around the triazole moiety were studied. We found that a cyclic amine group appended to the triazole ring could considerably enhance potency, aqueous solubility, and cell membrane permeability. Optimization of these cyclic amine groups led to the identification of 8-chloro-4-(3-chloro-4-fluorophenylamino)-6-((1-(1-ethylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)methylamino)quinoline-3-carbonitrile (34). In a LPS-stimulated rat inflammation model, compound 34 showed good efficacy in inhibiting TNF-alpha production.
Asunto(s)
Antiinflamatorios/química , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Nitrilos/química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Quinolinas/química , Factor de Necrosis Tumoral alfa/sangre , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacocinética , Femenino , Humanos , Lipopolisacáridos/farmacología , Quinasas Quinasa Quinasa PAM/metabolismo , Monocitos/efectos de los fármacos , Monocitos/inmunología , Nitrilos/síntesis química , Nitrilos/farmacocinética , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas/metabolismo , Quinolinas/síntesis química , Quinolinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
By focusing on the P1 portion of the piperidine beta-sulfone ligands we identified a motif that induces selectivity and resulted in a series of TACE inhibitors that demonstrated excellent in vitro potency against isolated TACE enzyme and excellent selectivity over MMPs 1, 2, 9, 13, and 14.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Proteínas ADAM/química , Inhibidores de Proteasas/química , Inhibidores de Proteasas/aislamiento & purificación , Proteína ADAM17 , Cristalografía por Rayos X , Ligandos , Metaloendopeptidasas/antagonistas & inhibidores , Piperidinas/química , Inhibidores de Proteasas/farmacología , Sulfonas/químicaRESUMEN
BACE1 is an aspartyl protease responsible for cleaving amyloid precursor protein to liberate Abeta, which aggregates leading to plaque deposits implicated in Alzheimer's disease. We have identified small-molecule acylguanidine inhibitors of BACE1. Crystallographic studies show that these compounds form unique hydrogen-bonding interactions with the catalytic site aspartic acids and stabilize the protein in a flap-open conformation. Structure-based optimization led to the identification of potent analogs, such as 10d (BACE1 IC(50) = 110 nM).
