Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
Más filtros

Bases de datos
Tipo de estudio
Tipo del documento
Intervalo de año de publicación
1.
Bioorg Med Chem Lett ; 44: 128115, 2021 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-34015507

RESUMEN

Kynurenine monooxygenase (KMO) is expected to be a good drug target to treat Huntington's disease (HD). This study presents the structure-activity relationship of pyridazine derivatives to find novel KMO inhibitors. The most promising compound 14 resolved the problematic issues of lead compound 1, i.e., metabolic instability and reactive metabolite-derived side-effects. Compound 14 exhibited high brain permeability and a long-lasting pharmacokinetics profile in monkeys, and neuroprotective kynurenic acid was increased by a single administration of 14 in R6/2 mouse brain. These results demonstrated 14 may be a potential drug candidate to treat HD.


Asunto(s)
Barrera Hematoencefálica/efectos de los fármacos , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Quinurenina 3-Monooxigenasa/antagonistas & inhibidores , Animales , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Humanos , Quinurenina 3-Monooxigenasa/metabolismo , Ratones , Estructura Molecular , Ratas , Relación Estructura-Actividad
2.
Bioorg Med Chem Lett ; 26(4): 1292-5, 2016 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-26786694

RESUMEN

We have designed and efficiently synthesized novel 1-phenyl-6-aminouracils by replacing the chroman moiety in CX-659S, a nonsteroidal dermatologic candidate, with dimethyldihydrobenzofuranol to cancel CX-659S asymmetric center. Medicinal chemistry effort culminated in the discovery of 13d bearing a 3-methyl group at the 1-phenyl group as a promising compound. Compound 13d, having good in vitro ADME profile and moderate oral bioavailability in mice, showed potent anti-inflammatory activity against hapten-induced contact hypersensitivity reaction in mice following topical and oral administration. The effects of 13d were equipotent to that of tacrolimus or prednisolone. In addition, compound 13d, having potent hydroxyl radical-scavenging activity, showed more potent suppressive effect on substance P-induced pruritus in mice than oxatomide.


Asunto(s)
Antiinflamatorios/síntesis química , Uracilo/análogos & derivados , Administración Oral , Animales , Antiinflamatorios/farmacocinética , Antiinflamatorios/uso terapéutico , Benzofuranos/química , Línea Celular Tumoral , Permeabilidad de la Membrana Celular , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/patología , Semivida , Humanos , Ratones , Microsomas/metabolismo , Prurito/tratamiento farmacológico , Ratas , Uracilo/química , Uracilo/farmacocinética , Uracilo/uso terapéutico
3.
Nat Chem Biol ; 8(12): 999-1007, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23103940

RESUMEN

The endocannabinoid 2-arachidonoylglycerol (2-AG) is biosynthesized by diacylglycerol lipases DAGLα and DAGLß. Chemical probes to perturb DAGLs are needed to characterize endocannabinoid function in biological processes. Here we report a series of 1,2,3-triazole urea inhibitors, along with paired negative-control and activity-based probes, for the functional analysis of DAGLß in living systems. Optimized inhibitors showed high selectivity for DAGLß over other serine hydrolases, including DAGLα (∼60-fold selectivity), and the limited off-targets, such as ABHD6, were also inhibited by the negative-control probe. Using these agents and Daglb(-/-) mice, we show that DAGLß inactivation lowers 2-AG, as well as arachidonic acid and eicosanoids, in mouse peritoneal macrophages in a manner that is distinct and complementary to disruption of cytosolic phospholipase-A2. We observed a corresponding reduction in lipopolysaccharide-induced tumor necrosis factor-α release. These findings indicate that DAGLß is a key metabolic hub within a lipid network that regulates proinflammatory responses in macrophages.


Asunto(s)
Inflamación/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Lipoproteína Lipasa/antagonistas & inhibidores , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/metabolismo , Animales , Ácido Araquidónico/metabolismo , Ácidos Araquidónicos/biosíntesis , Línea Celular , Citocinas/metabolismo , Descubrimiento de Drogas , Endocannabinoides/biosíntesis , Glicéridos/biosíntesis , Lipoproteína Lipasa/genética , Lipoproteína Lipasa/fisiología , Ratones , Ratones Noqueados , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Prostaglandinas/metabolismo , Isoformas de Proteínas , Proteoma/efectos de los fármacos , Relación Estructura-Actividad Cuantitativa , Transducción de Señal/efectos de los fármacos , Triazoles/síntesis química , Triazoles/farmacología , Factor de Necrosis Tumoral alfa/metabolismo
4.
J Am Chem Soc ; 134(25): 10345-8, 2012 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-22690931

RESUMEN

The development of small-molecule inhibitors for perturbing enzyme function requires assays to confirm that the inhibitors interact with their enzymatic targets in vivo. Determining target engagement in vivo can be particularly challenging for poorly characterized enzymes that lack known biomarkers (e.g., endogenous substrates and products) to report on their inhibition. Here, we describe a competitive activity-based protein profiling (ABPP) method for measuring the binding of reversible inhibitors to enzymes in animal models. Key to the success of this approach is the use of activity-based probes that show tempered rates of reactivity with enzymes, such that competition for target engagement with reversible inhibitors can be measured in vivo. We apply the competitive ABPP strategy to evaluate a newly described class of piperazine amide reversible inhibitors for the serine hydrolases LYPLA1 and LYPLA2, two enzymes for which selective, in vivo active inhibitors are lacking. Competitive ABPP identified individual piperazine amides that selectively inhibit LYPLA1 or LYPLA2 in mice. In summary, competitive ABPP adapted to operate with moderately reactive probes can assess the target engagement of reversible inhibitors in animal models to facilitate the discovery of small-molecule probes for characterizing enzyme function in vivo.


Asunto(s)
Amidas/química , Sistemas de Liberación de Medicamentos , Inhibidores Enzimáticos , Piperidinas/química , Bibliotecas de Moléculas Pequeñas/química , Animales , Unión Competitiva , Células Cultivadas , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Ratones , Estructura Molecular , Unión Proteica/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-Actividad
5.
J Am Chem Soc ; 133(41): 16605-16, 2011 Oct 19.
Artículo en Inglés | MEDLINE | ID: mdl-21899313

RESUMEN

Glutathione S-transferases (GSTs) are a superfamily of enzymes that conjugate glutathione to a wide variety of both exogenous and endogenous compounds for biotransformation and/or removal. Glutathione S-tranferase omega 1 (GSTO1) is highly expressed in human cancer cells, where it has been suggested to play a role in detoxification of chemotherapeutic agents. Selective inhibitors of GSTO1 are, however, required to test the role that this enzyme plays in cancer and other (patho)physiological processes. With this goal in mind, we performed a fluorescence polarization activity-based protein profiling (fluopol-ABPP) high-throughput screen (HTS) with GSTO1 and the Molecular Libraries Small Molecule Repository (MLSMR) 300K+ compound library. This screen identified a class of selective and irreversible α-chloroacetamide inhibitors of GSTO1, which were optimized to generate an agent KT53 that inactivates GSTO1 with excellent in vitro (IC(50) = 21 nM) and in situ (IC(50) = 35 nM) potency. Cancer cells treated with KT53 show heightened sensitivity to the cytotoxic effects of cisplatin, supporting a role for GSTO1 in chemotherapy resistance.


Asunto(s)
Antineoplásicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Glutatión Transferasa/antagonistas & inhibidores , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Proteínas Recombinantes/antagonistas & inhibidores , Estereoisomerismo , Relación Estructura-Actividad , Células Tumorales Cultivadas
6.
J Med Chem ; 56(21): 8257-69, 2013 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-24152245

RESUMEN

We have previously shown that 1,2,3-triazole ureas (1,2,3-TUs) act as versatile class of irreversible serine hydrolase inhibitors that can be tuned to create selective probes for diverse members of this large enzyme class, including diacylglycerol lipase-ß (DAGLß), a principal biosynthetic enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). Here, we provide a detailed account of the discovery, synthesis, and structure-activity relationship (SAR) of (2-substituted)-piperidyl-1,2,3-TUs that selectively inactivate DAGLß in living systems. Key to success was the use of activity-based protein profiling (ABPP) with broad-spectrum and tailored activity-based probes to guide our medicinal chemistry efforts. We also describe an expanded repertoire of DAGL-tailored activity-based probes that includes biotinylated and alkyne agents for enzyme enrichment coupled with mass spectrometry-based proteomics and assessment of proteome-wide selectivity. Our findings highlight the broad utility of 1,2,3-TUs for serine hydrolase inhibitor development and their application to create selective probes of endocannabinoid biosynthetic pathways.


Asunto(s)
Descubrimiento de Drogas , Endocannabinoides/biosíntesis , Inhibidores Enzimáticos/farmacología , Piperidinas/farmacología , Triazoles/farmacología , Urea/farmacología , Relación Dosis-Respuesta a Droga , Endocannabinoides/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Humanos , Lipoproteína Lipasa/antagonistas & inhibidores , Lipoproteína Lipasa/metabolismo , Estructura Molecular , Piperidinas/química , Piperidinas/metabolismo , Relación Estructura-Actividad , Triazoles/química , Triazoles/metabolismo , Urea/análogos & derivados , Urea/química
7.
J Med Chem ; 56(21): 8270-9, 2013 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-24152295

RESUMEN

α/ß-Hydrolase domain containing 6 (ABHD6) is a transmembrane serine hydrolase that hydrolyzes the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) to regulate certain forms of cannabinoid receptor-dependent signaling in the nervous system. The full spectrum of ABHD6 metabolic activities and functions is currently unknown and would benefit from selective, in vivo-active inhibitors. Here, we report the development and characterization of an advanced series of irreversible (2-substituted)-piperidyl-1,2,3-triazole urea inhibitors of ABHD6, including compounds KT182 and KT203, which show exceptional potency and selectivity in cells (<5 nM) and, at equivalent doses in mice (1 mg kg(-1)), act as systemic and peripherally restricted ABHD6 inhibitors, respectively. We also describe an orally bioavailable ABHD6 inhibitor, KT185, that displays excellent selectivity against other brain and liver serine hydrolases in vivo. We thus describe several chemical probes for biological studies of ABHD6, including brain-penetrant and peripherally restricted inhibitors that should prove of value for interrogating ABHD6 function in animal models.


Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Monoacilglicerol Lipasas/antagonistas & inhibidores , Animales , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Humanos , Ratones , Modelos Animales , Estructura Molecular , Monoacilglicerol Lipasas/metabolismo , Piperidinas/química , Piperidinas/metabolismo , Piperidinas/farmacología , Relación Estructura-Actividad , Triazoles/química , Triazoles/metabolismo , Triazoles/farmacología , Urea/análogos & derivados , Urea/química , Urea/farmacología
8.
Chem Asian J ; 2(3): 377-85, 2007 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-17441173

RESUMEN

We have accomplished the synthesis of 13C-labeled tautomycin at the C18, C19, C21, and C22 positions starting from 100% [13C]triethylphosphonoacetate for the purpose of elucidating the dynamics and conformation of the C17-C26 moiety. NMR spectroscopy of 13C-labeled tautomycin revealed strong binding with protein phosphatase type 1 and new features in the 13C NMR spectrum, such as the very small three-bond coupling constants (2J).


Asunto(s)
Inhibidores Enzimáticos/síntesis química , Marcaje Isotópico , Espectroscopía de Resonancia Magnética/métodos , Fosfoproteínas Fosfatasas/antagonistas & inhibidores , Piranos/síntesis química , Compuestos de Espiro/síntesis química , Isótopos de Carbono , Piranos/química , Compuestos de Espiro/química
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA