RESUMEN
Classic Galactosemia is a rare inborn error of metabolism that is caused by deficiency of galactose-1-phosphate uridyltransferase (GALT), an enzyme within the Leloir pathway that is responsible for the conversion of galactose-1-phosphate (gal-1-p) and UDP-glucose to glucose-1-phosphate and UDP-galactose. This deficiency results in elevated intracellular concentrations of its substrate, gal-1-p, and this increased concentration is believed to be the major pathogenic mechanism in Classic Galactosemia. Galactokinase (GALK) is an upstream enzyme of GALT in the Leloir pathway and is responsible for conversion of galactose and ATP to gal-1-p and ADP. Therefore, it was hypothesized that the identification of a small-molecule inhibitor of human GALK would act to prevent the accumulation of gal-1-p and offer a novel entry therapy for this disorder. Herein we describe a quantitative high-throughput screening campaign that identified a single chemotype that was optimized and validated as a GALK inhibitor.
Asunto(s)
Galactoquinasa/antagonistas & inhibidores , Animales , Benzoxazoles/síntesis química , Benzoxazoles/química , Benzoxazoles/metabolismo , Cristalografía por Rayos X , Galactoquinasa/genética , Galactoquinasa/metabolismo , Galactosafosfatos/metabolismo , Ensayos Analíticos de Alto Rendimiento , Humanos , Cinética , Ratones , Microsomas Hepáticos/metabolismo , Conformación Molecular , Unión Proteica , Ratas , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Compuestos de Espiro/química , Relación Estructura-ActividadRESUMEN
Employing an iterative analogue library approach, novel potent and selective glycine transporter 1 (GlyT1) inhibitors containing a 4-pyridin-2-ylpiperidine sulfonamide have been discovered. These inhibitors are devoid of time-dependent CYP inhibition activity and exhibit improved aqueous solubility versus the corresponding 4-phenylpiperidine analogues.
Asunto(s)
Benzamidas/síntesis química , Descubrimiento de Drogas/métodos , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Piperidinas/síntesis química , Sulfonamidas/síntesis química , Benzamidas/farmacología , Proteínas de Transporte de Glicina en la Membrana Plasmática/metabolismo , Humanos , Piperidinas/farmacología , Solubilidad , Sulfonamidas/farmacologíaRESUMEN
Glycine transporter 1 (GlyT1) represents a novel target for the treatment of schizophrenia via the potentiation of glutamatergic NMDA receptors. The discovery of 4,4-disubstituted piperidine inhibitors of GlyT1 which exhibit improved pharmacokinetic properties, including oral bioavailability, is discussed.
Asunto(s)
Descubrimiento de Drogas/métodos , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Piperidinas/síntesis química , Piperidinas/farmacocinética , Animales , Perros , Glicina/biosíntesis , Proteínas de Transporte de Glicina en la Membrana Plasmática/metabolismo , Humanos , Ratones , Ratones Endogámicos DBA , N-Metilaspartato/química , N-Metilaspartato/farmacología , Piperidinas/administración & dosificación , Ratas , Especificidad por Sustrato , Sulfonamidas/síntesis químicaRESUMEN
Butabindide, 1, was previously reported as a potent inhibitor (IC50 = 7 nM) of the serine protease enzyme tripeptidyl peptidase II (TPPII), an endogenous protease that degrades cholecystokinin-8 (CCK-8). We found that 1 has some inherent chemical instability, yielding diketopiperazine 2 fairly readily under mimicked physiological conditions. We therefore prepared imidazoles 3, which are void of 1's inherent instability, and have found that our novel analogues maintained comparable TPPII inhibitory activity (e.g.,for 3c, IC50 = 4 nM) as 1.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Imidazoles/síntesis química , Indoles/síntesis química , Serina Endopeptidasas/química , Inhibidores de Serina Proteinasa/síntesis química , Aminopeptidasas , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas , Inhibidores Enzimáticos/química , Imidazoles/química , Indoles/química , Modelos Moleculares , Inhibidores de Serina Proteinasa/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
This report describes the discovery of the first centrally active allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5). Appropriately substituted N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides (e.g., 8) have been identified as a novel class of potent positive allosteric modulators of mGluR5 that potentiate the response to glutamate. An iterative analogue library synthesis approach provided potentiators with excellent potency and selectivity for mGluR5 (vs mGluRs 1-4, 7, 8). Compound 8q demonstrated in vivo proof of concept in an animal behavior model where known antipsychotics are active, supporting the development of new antipsychotics based on the NMDA hypofunction model for schizophrenia.
Asunto(s)
Benzamidas/síntesis química , Pirazoles/síntesis química , Receptores de Glutamato Metabotrópico/efectos de los fármacos , Regulación Alostérica , Animales , Antipsicóticos/síntesis química , Antipsicóticos/química , Antipsicóticos/farmacología , Benzamidas/química , Benzamidas/farmacología , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Ácido Glutámico/farmacología , Humanos , Técnicas In Vitro , Pirazoles/química , Pirazoles/farmacología , Ratas , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/fisiología , Reflejo de Sobresalto/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
[reaction: see text] A simple, high-yielding synthesis of 2,4,5-trisubstituted imidazoles from 1,2-diketones and aldehydes in the presence of NH(4)OAc is described. Under microwave irradiation, alkyl-, aryl-, and heteroaryl-substituted imidazoles are formed in yields ranging from 80 to 99%. Short syntheses of lepidiline B and trifenagrel illustrate the utility of this approach.
Asunto(s)
Aldehídos/química , Imidazoles/síntesis química , Cetonas/química , Microondas , Aldehídos/síntesis química , Aldehídos/efectos de la radiación , Cetonas/síntesis química , Cetonas/efectos de la radiación , Estructura MolecularRESUMEN
This letter describes the discovery of a novel series of dual Akt1/Akt2 kinase inhibitors, based on a 2,3,5-trisubstituted pyridine scaffold. Compounds from this series, which contain a 5-tetrazolyl moiety, exhibit more potent inhibition of Akt2 than Akt1.
Asunto(s)
Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Piridinas/química , Piridinas/farmacología , Animales , Permeabilidad de la Membrana Celular , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Proteínas Proto-Oncogénicas c-akt , Piridinas/farmacocinética , Relación Estructura-ActividadRESUMEN
This letter describes the development of two series of potent and selective allosteric Akt kinase inhibitors that display an unprecedented level of selectivity for either Akt1, Akt2 or both Akt1/Akt2. An iterative analog library synthesis approach quickly provided a highly selective Akt1/Akt2 inhibitor that induces apoptosis in tumor cells and inhibits Akt phosphorylation in vivo.