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1.
BMC Genomics ; 20(1): 938, 2019 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-31805873

RESUMEN

BACKGROUND: Spinibarbus hollandi is an economically important fish species in southern China. This fish is known to have nutritional and medicinal properties; however, its farming is limited by its slow growth rate. In the present study, we observed that a compensatory growth phenomenon could be induced by adequate refeeding following 7 days of fasting in S. hollandi. To understand the starvation response and compensatory growth mechanisms in this fish, the muscle transcriptomes of S. hollandi under control, fasting, and refeeding conditions were profiled using next-generation sequencing (NGS) techniques. RESULTS: More than 4.45 × 108 quality-filtered 150-base-pair Illumina reads were obtained from all nine muscle samples. De novo assemblies yielded a total of 156,735 unigenes, among which 142,918 (91.18%) could be annotated in at least one available database. After 7 days of fasting, 2422 differentially expressed genes were detected, including 1510 up-regulated genes and 912 down-regulated genes. Genes involved in fat, protein, and carbohydrate metabolism were significantly up-regulated, and genes associated with the cell cycle, DNA replication, and immune and cellular structures were inhibited during fasting. After refeeding, 84 up-regulated genes and 16 down-regulated genes were identified. Many genes encoding the components of myofibers were significantly up-regulated. Histological analysis of muscle verified the important role of muscle hypertrophy in compensatory growth. CONCLUSION: In the present work, we reported the transcriptome profiles of S. hollandi muscle under different conditions. During fasting, the genes involved in the mobilization of stored energy were up-regulated, while the genes associated with growth were down-regulated. After refeeding, muscle hypertrophy contributed to the recovery of growth. The results of this study may help to elucidate the mechanisms underlying the starvation response and compensatory growth.


Asunto(s)
Cyprinidae/crecimiento & desarrollo , Perfilación de la Expresión Génica/veterinaria , Redes Reguladoras de Genes , Músculo Esquelético/crecimiento & desarrollo , Animales , Cyprinidae/genética , Ayuno , Conducta Alimentaria , Proteínas de Peces/genética , Regulación del Desarrollo de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento/veterinaria , Músculo Esquelético/química , Análisis de Secuencia de ARN/veterinaria
2.
Bioorg Med Chem Lett ; 26(8): 1901-4, 2016 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-26988301

RESUMEN

The identification of a low-permeability scavenger receptor BI (SR-BI) inhibitor starting from the ITX-5061 template is described. Structure-activity and structure-permeability relationships were assessed for analogs leading to the identification of compound 8 as a potent and nonabsorbable SR-BI inhibitor.


Asunto(s)
Fenilendiaminas/farmacología , Receptores Depuradores de Clase B/antagonistas & inhibidores , Sulfonamidas/farmacología , Animales , Perros , Relación Dosis-Respuesta a Droga , Humanos , Células de Riñón Canino Madin Darby , Estructura Molecular , Especificidad de Órganos , Fenilendiaminas/administración & dosificación , Fenilendiaminas/química , Ratas , Relación Estructura-Actividad , Sulfonamidas/administración & dosificación , Sulfonamidas/química
3.
PLoS One ; 14(3): e0214589, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30921420

RESUMEN

Starvation is a common stress in fish. The underlying molecular mechanisms associated with growth depression caused by feeding restriction and compensatory growth are not well understood. We investigated the effect of fasting and refeeding on the transcriptome profiles of brain in juvenile S. hollandi using RNA-seq. A total of 4.73 × 108 raw reads were obtained from nine brain samples. De novo transcriptome assembly identified 387,085 unigenes with 2.1×109 nucleotides. A total of 936 annotated unigenes showed significantly differential expression among the control, fasting, and fasting-refeeding groups. The down-regulated differentially expressed genes (DEGs) during fasting were mainly associated with cell cycle, DNA replication, and mitosis. The up-regulated DEGs were mainly related to glucose and lipid metabolism, material transportation, and transcription factors. Most decreased DEGs during fasting were restored to normal levels after refeeding. Comparing with the control group, genes associated with protein synthesis, stimulus response, and carbohydrate metabolism were significantly over-expressed and pro-opio melanocortin (POMC) was down-regulated during the refeeding period. In conclusion, fish mobilized stored energetic materials and reduced energy consumption to prolong survival during fasting. After refeeding, the down-regulation of DEGs, e.g., POMC may be associated with compensatory growth. Up-regulation of DEGs related to ribosomal protein, stimulus response, and carbohydrate metabolism may contribute to eliminate negative effect of starvation on brain. This study provided the first transcriptome data related with impact of short-time starvation and refeeding in S. hollandi brains.


Asunto(s)
Encéfalo/metabolismo , Cyprinidae/genética , Ingestión de Alimentos/genética , Ayuno , Perfilación de la Expresión Génica , Animales , Peso Corporal/genética , Cyprinidae/crecimiento & desarrollo , Inanición/genética
4.
ACS Med Chem Lett ; 10(11): 1518-1523, 2019 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-31749904

RESUMEN

Herein we report the discovery of pyrazolocarboxamides as novel, potent, and kinase selective inhibitors of receptor interacting protein 2 kinase (RIP2). Fragment based screening and design principles led to the identification of the inhibitor series, and X-ray crystallography was used to inform key structural changes. Through key substitutions about the N1 and C5 N positions on the pyrazole ring significant kinase selectivity and potency were achieved. Bridged bicyclic pyrazolocarboxamide 11 represents a selective and potent inhibitor of RIP2 and will allow for a more detailed investigation of RIP2 inhibition as a therapeutic target for autoinflammatory disorders.

5.
Genes Genomics ; 40(11): 1119-1125, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30315516

RESUMEN

Melanocortin 4 receptor: (MC4R) and Myostatin (MSTN) are two important growth trait-related genes in animals. In this study, we showed that two SNPs, MC4R-719A>G and MSTN-519C>T, found in the promoters of the MC4R and MSTN genes, respectively, are both associated with growth traits in Spinibarbus hollandi. Furthermore, we observed that there were significant associations between the expression levels of the MC4R and MSTN genes and these two growth trait-related SNPs. The expression level of MC4R gene in brain was lower in GG genotype fish with extremely high growth performance than that in AA genotype fish with extremely low growth performance. Expression level of the MSTN gene in muscle was lower in TT genotype fish with extremely high growth performance than that in CC and CT genotype fish with lower growth performance. The results indicated that these SNPs located in the promoters of MC4R and MSTN are associated with growth-related traits through modification of gene expression levels. The MSTN and MC4R SNPs may have useful application in effective marker-assisted selection aimed to increase output in S. hollandi.


Asunto(s)
Cyprinidae/genética , Miostatina/genética , Polimorfismo de Nucleótido Simple , Receptor de Melanocortina Tipo 4/genética , Animales , Cyprinidae/crecimiento & desarrollo , Cyprinidae/metabolismo , Expresión Génica , Miostatina/metabolismo , Regiones Promotoras Genéticas , Receptor de Melanocortina Tipo 4/metabolismo
6.
J Med Chem ; 49(24): 7215-26, 2006 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-17125274

RESUMEN

We report the application of phosphoramidate pronucleotide (ProTide) technology to the antiviral agent carbocyclic L-d4A (L-Cd4A). The phenyl methyl alaninyl parent ProTide of L-Cd4A was prepared by Grignard-mediated phosphorochloridate reaction and resulted in a compound with significantly improved anti-HIV (2600-fold) and HBV activity. We describe modifications of the aryl, ester, and amino acid regions of the ProTide and how these changes affect antiviral activity and metabolic stability. Separate and distinct SARs were noted for HIV and HBV. Additionally, ProTides were prepared from the D-nucleoside D-Cd4A and the dideoxy analogues L-CddA and D-CddA. These compounds showed more modest potency improvements over the parent drug. In conclusion, the ProTide approach is highly successful when applied to L-Cd4A with potency improvements in vitro as high as 9000-fold against HIV. With a view to preclinical candidate selection we carried out metabolic stability studies using cynomolgus monkey liver and intestinal S9 fractions.


Asunto(s)
Adenosina/análogos & derivados , Adenosina/síntesis química , Antivirales/síntesis química , Compuestos Organofosforados/síntesis química , Adenosina/farmacología , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Antivirales/farmacología , Línea Celular , VIH-1/efectos de los fármacos , VIH-2/efectos de los fármacos , Virus de la Hepatitis B/efectos de los fármacos , Humanos , Técnicas In Vitro , Mucosa Intestinal/metabolismo , Hígado/metabolismo , Nucleótidos/síntesis química , Nucleótidos/farmacología , Compuestos Organofosforados/farmacología , Relación Estructura-Actividad
7.
J Med Chem ; 49(24): 7095-107, 2006 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-17125262

RESUMEN

The high expression of MCH in the hypothalamus with the lean hypophagic phenotype coupled with increased resting metabolic rate and resistance to high fat diet-induced obesity of MCH KO mice has spurred considerable efforts to develop small molecule MCHR1 antagonists. Starting from a lead thienopyrimidinone series, structure-activity studies at the 3- and 6-positions of the thienopyrimidinone core afforded potent and selective MCHR1 antagonists with representative examples having suitable pharmacokinetic properties. Based on structure-activity relationships, a structural model for MCHR1 was constructed to explain the binding mode of these antagonists. In general, a good correlation was observed between pKas and activity in the right-hand side of the template, with Asp123 playing an important role in the enhancement of binding affinity. A representative example when evaluated chronically in diet-induced obese mice resulted in good weight loss effects. These antagonists provide a viable lead series in the discovery of new therapies for the treatment of obesity.


Asunto(s)
Fármacos Antiobesidad/síntesis química , Pirimidinas/síntesis química , Receptores de Somatostatina/antagonistas & inhibidores , Tiofenos/síntesis química , Administración Oral , Animales , Fármacos Antiobesidad/química , Fármacos Antiobesidad/farmacología , Disponibilidad Biológica , Células CHO , Cricetinae , Cricetulus , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Canales de Potasio Éter-A-Go-Go/fisiología , Genes Reporteros , Semivida , Humanos , Ratones , Ratones Obesos , Modelos Moleculares , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacología
8.
J Med Chem ; 49(24): 7108-18, 2006 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-17125263

RESUMEN

Genetic manipulation studies in mice at both the MCH receptor 1 (MCHR1) as well as the MCH peptide levels have implicated MCHR1 as a key player in energy homeostasis. The phenotype exhibited by these studies, that is, increased metabolic rate, resistance to high fat diet, and subsequent weight loss, has spurred considerable efforts to develop antagonists of MCHR1. In continuation of efforts directed toward this goal, the present work capitalizes on the putative binding mode of an MCH antagonist, resulting in the identification of several novel chemotypes that are potent and selective MCHR1 antagonists. In addition, the favorable pharmacokinetics of representative examples has allowed for the evaluation of an MCHR1 antagonist in a high fat diet-induced obese rodent model of obesity. The tolerability of the right-hand side of the template for diverse chemotypes accompanied by favorable effects on weight loss enhances the attractiveness of this template in the pursuit toward development of effective anti-obesity agents.


Asunto(s)
Fármacos Antiobesidad/síntesis química , Pirimidinas/síntesis química , Receptores de Somatostatina/antagonistas & inhibidores , Tiofenos/síntesis química , Animales , Fármacos Antiobesidad/farmacocinética , Fármacos Antiobesidad/farmacología , Sitios de Unión , Células CHO , Cricetinae , Cricetulus , Ratones , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ratas , Receptores de Somatostatina/química , Relación Estructura-Actividad , Tiofenos/farmacocinética , Tiofenos/farmacología
9.
J Med Chem ; 47(21): 5049-56, 2004 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-15456248

RESUMEN

Cathepsin K, a lysosomal cysteine protease of the papain superfamily, is abundantly and selectively expressed in osteoclasts, suggesting that this enzyme is crucial for bone resorption. Prevention of osteoclast-mediated bone resorption via inhibition of cathepsin K could be an effective approach to prevent osteoporosis. Potent and selective reversible ketoamide-based inhibitors have been identified in the present study. Using a known crystal structure of a ketoamide-based inhibitor, information from residues that form the P2/P3 pocket was used in the design of inhibitors that could allow for gains in selectivity and potency. Further, incorporation of P' selective heterocycles, along with the P2/P3 modifications, is also described. These modifications have resulted in potent and selective cathepsin K inhibitors that allow for improvements in their physiochemical properties and represent a viable lead series for the discovery of new therapies for the prevention and treatment of osteoporosis


Asunto(s)
Amidas/síntesis química , Catepsinas/antagonistas & inhibidores , Cetonas/síntesis química , Amidas/química , Carbamatos/síntesis química , Carbamatos/química , Catepsina K , Catepsinas/química , Ciclobutanos/síntesis química , Ciclobutanos/química , Ciclopentanos/síntesis química , Ciclopentanos/química , Cetonas/química , Modelos Moleculares , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-Actividad
10.
J Med Chem ; 47(19): 4716-30, 2004 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-15341487

RESUMEN

Glycogen synthase kinase 3 regulates glycogen synthase, the rate-determining enzyme for glycogen synthesis. Liver and muscle glycogen synthesis is defective in type 2 diabetics, resulting in elevated plasma glucose levels. Inhibition of GSK-3 could potentially be an effective method to control plasma glucose levels in type 2 diabetics. Structure-activity studies on a N-phenyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amine series have led to the identification of potent and selective compounds with good cellular efficacy. Molecular modeling studies have given insights into the mode of binding of these inhibitors. Since the initial leads were also potent inhibitors of CDK-2/CDK-4, an extensive SAR was performed at various positions of the pyrazolo[1,5-b]pyridazin core to afford potent GSK-3 inhibitors that were highly selective over CDK-2. In addition, these inhibitors also exhibited very good cell efficacy and functional response. A representative example was shown to have good oral exposure levels, extending their utility in an in vivo setting. These inhibitors provide a viable lead series in the discovery of new therapies for the treatment of type 2 diabetes.


Asunto(s)
Aminas/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Piridazinas/química , Piridazinas/farmacología , Animales , Sitios de Unión , Línea Celular , Inhibidores Enzimáticos/síntesis química , Glucógeno Sintasa Quinasa 3/metabolismo , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Estructura Terciaria de Proteína , Piridazinas/síntesis química , Ratas , Relación Estructura-Actividad
11.
J Med Chem ; 47(3): 588-99, 2004 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-14736240

RESUMEN

Osteoclast-mediated bone matrix resorption has been attributed to cathepsin K, a cysteine protease of the papain family that is abundantly and selectively expressed in osteoclast. Inhibition of cathepsin K could potentially be an effective method to prevent osteoporosis. Structure-activity studies on a series of reversible ketoamides based inhibitors of cathepsin K have led to identification of potent and selective compounds. Crystallographic studies have given insights into the mode of binding of these inhibitors. A series of ketoamides with varying P1 moieties were first synthesized to find an optimum group that would fit into the S1 subsite of the cysteine protease, cathepsin K. With a desired P1 group in place a variety of heterocyclic analogues in the P' region were synthesized to study their steric and electronic effects. In the process of exploring these P' heterocyclic variations, excellent selectivity was gained over other highly homologous cysteine proteases, including cathepsins L, S, and V. The favorable pharmacokinetic properties of some of these cathepsin K inhibitors in rats make them suitable for evaluation in rodent osteoporosis models. A representative cathepsin K inhibitor was shown to attenuate PTH-stimulated hypercalcemia in the TPTX rat model. These inhibitors provide a viable lead series in the discovery of new therapies for the prevention and treatment of osteoporosis


Asunto(s)
Amidas/síntesis química , Catepsinas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/síntesis química , Cetonas/síntesis química , Administración Oral , Amidas/farmacocinética , Amidas/farmacología , Animales , Disponibilidad Biológica , Calcio/sangre , Catepsina K , Catepsinas/química , Cristalografía por Rayos X , Inhibidores de Cisteína Proteinasa/farmacocinética , Inhibidores de Cisteína Proteinasa/farmacología , Humanos , Cetonas/farmacocinética , Cetonas/farmacología , Masculino , Modelos Moleculares , Estructura Molecular , Osteoporosis/metabolismo , Ratas , Ratas Wistar , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/química , Relación Estructura-Actividad
13.
ACS Med Chem Lett ; 1(1): 19-23, 2010 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-24900169

RESUMEN

A series of benzisothiazole- and indolizine-ß-d-glucopyranoside inhibitors of human SGLT2 are described. The synthesis of the C-linked heterocyclic glucosides took advantage of a palladium-catalyzed cross-coupling reaction between a glucal boronate and the corresponding bromo heterocycle. The compounds have been evaluated for their human SGLT2 inhibition potential using cell-based functional transporter assays, and their structure-activity relationships have been described. Benzisothiazole-C-glucoside 16d was found to be an inhibitor of SGLT2 with an IC50 of 10 nM.

16.
Bioorg Med Chem Lett ; 15(15): 3540-6, 2005 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-15982880

RESUMEN

An orally bioavailable series of ketoamide-based cathepsin K inhibitors with good pharmacokinetic properties has been identified. Starting from a potent inhibitor endowed with poor drug properties, conformational constraint of the P(2)-P(3) linker and modifications to P(1') elements led to an enhancement in potency, solubility, clearance, and bioavailability. These optimized inhibitors attenuated bone resorption in a rat TPTX hypocalcemic bone resorption model.


Asunto(s)
Amidas/síntesis química , Catepsinas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/síntesis química , Cetonas/síntesis química , Amidas/farmacocinética , Amidas/farmacología , Animales , Sitios de Unión , Disponibilidad Biológica , Resorción Ósea/tratamiento farmacológico , Resorción Ósea/metabolismo , Catepsina K , Catepsinas/química , Inhibidores de Cisteína Proteinasa/farmacocinética , Inhibidores de Cisteína Proteinasa/farmacología , Modelos Animales de Enfermedad , Hipocalcemia/tratamiento farmacológico , Hipocalcemia/metabolismo , Cetonas/farmacocinética , Cetonas/farmacología , Ratas , Ratas Wistar , Solubilidad , Relación Estructura-Actividad
17.
Bioorg Med Chem Lett ; 14(10): 2543-6, 2004 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-15109647

RESUMEN

An orally available series of ketoamide-based inhibitors of cathepsin K has been identified. Starting from a potent inhibitor with poor oral bioavailability, modifications to P1 and P1' elements led to enhancements in solubility and permeability. These improvements resulted in orally available cathepsin K inhibitors.


Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Catepsinas/antagonistas & inhibidores , Administración Oral , Amidas/administración & dosificación , Animales , Disponibilidad Biológica , Catepsina K , Línea Celular , Perros , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Concentración 50 Inhibidora , Farmacocinética , Relación Estructura-Actividad
18.
Bioorg Med Chem Lett ; 14(9): 2121-5, 2004 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-15080992

RESUMEN

A series of [1-aryl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]arylhydrazones were discovered as novel inhibitors glycogen synthase kinase-3 (GSK-3). Based on initial modeling a detailed SAR was constructed. Modification of the interior binding aryl ring (Ar(1)) determined this to be a tight binding region with little room for modification. As predicted from the model, a large variety of modifications could be incorporated into the hydrazone aryl ring. This work led to GSK-3 inhibitors in the low nano-molar range.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Pirazoles/química , Pirimidinas/farmacología , Inhibidores Enzimáticos/química , Modelos Moleculares , Pirimidinas/química
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