RESUMEN
Sortilin is a type I membrane glycoprotein belonging to the vacuolar protein sorting 10 protein (Vps10p) family of sorting receptors and is most abundantly expressed in the central nervous system. Sortilin has emerged as a key player in the regulation of neuronal viability and has been implicated as a possible therapeutic target in a range of disorders. Here, the identification of AF40431, the first reported small-molecule ligand of sortilin, is reported. Crystals of the sortilin-AF40431 complex were obtained by co-crystallization and the structure of the complex was solved to 2.7â Å resolution. AF40431 is bound in the neurotensin-binding site of sortilin, with the leucine moiety of AF40431 mimicking the binding mode of the C-terminal leucine of neurotensin and the 4-methylumbelliferone moiety of AF40431 forming π-stacking with a phenylalanine.
Asunto(s)
Proteínas Adaptadoras del Transporte Vesicular/antagonistas & inhibidores , Proteínas Adaptadoras del Transporte Vesicular/química , Cumarinas/química , Leucina/análogos & derivados , Bibliotecas de Moléculas Pequeñas/química , Proteínas Adaptadoras del Transporte Vesicular/genética , Sitios de Unión , Cristalización , Cristalografía por Rayos X , Células HEK293 , Humanos , Leucina/química , Ligandos , Neurotensina/química , Fenilalanina/química , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Relación Estructura-ActividadRESUMEN
In this Letter, we describe a chemical lead optimization campaign starting from a novel, weak α7 nicotinic acetylcholine receptor positive allosteric modulator (PAM) hit from a HTS screen. Exploration of the structure-activity relationships for α7 PAM potency, intrinsic hepatic clearance, the structure-property relationships for lipophilicity, and thermodynamic solubility, led to the identification of Lu AF58801: a potent, orally available, brain penetrant PAM of the α7 nicotinic acetylcholine receptor, showing efficacy in a novel object recognition task in rats treated subchronically with phencyclidine (PCP).
Asunto(s)
Encéfalo/efectos de los fármacos , Trastornos del Conocimiento/tratamiento farmacológico , Ciclopropanos/farmacología , Descubrimiento de Drogas , Alcohol Feniletílico/análogos & derivados , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Administración Oral , Regulación Alostérica/efectos de los fármacos , Animales , Encéfalo/metabolismo , Trastornos del Conocimiento/inducido químicamente , Ciclopropanos/administración & dosificación , Ciclopropanos/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Fenciclidina/administración & dosificación , Alcohol Feniletílico/administración & dosificación , Alcohol Feniletílico/química , Alcohol Feniletílico/farmacología , Ratas , Ratas Endogámicas , Relación Estructura-ActividadRESUMEN
The identification of the novel, selective, orally bioavailable Sortilin inhibitor AF38469 is described. Structure-activity relationships and syntheses are reported, along with an X-ray crystal structure of the sortilin-AF38469 protein-inhibitor complex.
Asunto(s)
Proteínas Adaptadoras del Transporte Vesicular/antagonistas & inhibidores , Hidrocarburos Fluorados/farmacología , Piridinas/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos Analíticos de Alto Rendimiento , Hidrocarburos Fluorados/síntesis química , Hidrocarburos Fluorados/química , Modelos Moleculares , Estructura Molecular , Piridinas/síntesis química , Piridinas/química , Ratas , Relación Estructura-ActividadRESUMEN
Elevation of glycine levels by inhibition of the glycine transporter-1 (GlyT-1) and activation of the NMDA receptor is a potential strategy for the treatment of schizophrenia. A novel series of 2-arylsulfanylphenyl-1-oxyalkyl amino acids have been identified. The most prominent member of this series S-1-{2-[3-(3-fluoro-phenylsulfanyl)biphenyl-4-yloxy]ethyl}pyrrolidine-2-carboxylic acid (38) is a potent GlyT-1 inhibitor (IC50=59 nM). In vitro and in vivo assessment of CNS exposure indicates this compound is a likely substrate for active efflux transporters.
Asunto(s)
Aminoácidos/síntesis química , Aminoácidos/farmacología , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Aminoácidos/química , Aminoácidos/farmacocinética , Barrera Hematoencefálica , Células CACO-2 , Humanos , Relación Estructura-ActividadRESUMEN
A range of 3,5-diarylated and 3,4,5-triarylated 2-(4-methoxybenzyl)pyrazole 1-oxides have been prepared by regioselective deprotonation at C-5 or bromine-magnesium exchange at C-3 or C-4 followed by transmetalation with ZnCl(2) and palladium(0)-catalyzed cross-coupling. Furthermore, the metalated pyrazole 1-oxides could be trapped with electrophiles. The sequential metalation/functionalization of the pyrazole 1-oxides may follow the order C-5, C-3, C-4, or alternatively the order C-3, C-5, C-4. The 4-methoxybenzyl group of the functionalized 2-(4-methoxybenzyl)pyrazole 1-oxides could be removed by treatment with TFA and i-Pr(3)SiH in CH(2)Cl(2), providing the corresponding functionalized 1-hydroxypyrazoles.