Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 67
Filtrar
Más filtros

Bases de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
J Nat Med ; 75(2): 261-274, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33274411

RESUMEN

Natural products, which can be isolated from living organisms worldwide, have played a pivotal role in drug discovery since ancient times. However, it has become more challenging to identify a structurally novel molecule with promising biological activity for pharmaceutical development, mainly due to the limited methodologies for their acquisition. In this review, we summarize our recent studies that activate the biosynthetic potential of filamentous fungi by genetic engineering to harness the metabolic flow for the efficient production of unprecedented natural products. The recent revolution in genome sequencing technology enables the accumulation of vast amounts of information on biosynthetic genes, the blueprint of the molecular construction. Utilizing the established heterologous expression system, activation of the pathway-specific transcription factor coupled with a knockout strategy, and manipulating the global regulatory gene, the biosynthetic genes were exploited to activate biosynthetic pathways and decipher the encoded enzyme functions. We show that this methodology was beneficial for acquiring fungal treasures for drug discovery. These studies also enabled the investigation of the molecular function of natural products in fungal development.


Asunto(s)
Vías Biosintéticas/genética , Genómica/métodos , Compuestos de Espiro/uso terapéutico , Productos Biológicos/farmacología , Humanos , Estructura Molecular , Compuestos de Espiro/farmacología
2.
J Med Chem ; 63(24): 15508-15526, 2020 12 24.
Artículo en Inglés | MEDLINE | ID: mdl-33064947

RESUMEN

The synthesis and pharmacological activity of a new series of 4-alkyl-1-oxa-4,9-diazaspiro[5.5]undecane derivatives as potent dual ligands for the σ1 receptor (σ1R) and the µ-opioid receptor (MOR) are reported. A lead optimization program over the initial 4-aryl analogues provided 4-alkyl derivatives with the desired functionality and good selectivity and ADME profiles. Compound 14u (EST73502) showed MOR agonism and σ1R antagonism and a potent analgesic activity, comparable to the MOR agonist oxycodone in animal models of acute and chronic pain after single and repeated administration. Contrary to oxycodone, 14u produces analgesic activity with reduced opioid-induced relevant adverse events, like intestinal transit inhibition and naloxone-precipitated behavioral signs of opiate withdrawal. These results provide evidence that dual MOR agonism and σ1R antagonism may be a useful strategy for obtaining potent and safer analgesics and were the basis for the selection of 14u as a clinical candidate for the treatment of pain.


Asunto(s)
Analgésicos Opioides/química , Receptores Opioides mu/agonistas , Receptores sigma/antagonistas & inhibidores , Administración Oral , Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacología , Analgésicos Opioides/uso terapéutico , Animales , Sitios de Unión , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Semivida , Ligandos , Masculino , Ratones , Simulación de Dinámica Molecular , Dolor/tratamiento farmacológico , Receptores Opioides mu/metabolismo , Receptores sigma/metabolismo , Compuestos de Espiro/química , Compuestos de Espiro/metabolismo , Compuestos de Espiro/farmacología , Compuestos de Espiro/uso terapéutico , Relación Estructura-Actividad , Receptor Sigma-1
3.
4.
Exp Biol Med (Maywood) ; 245(18): 1722-1731, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32878462

RESUMEN

Acupuncture is an emerging alternative therapy that has been beneficial for the pain of osteoarthritis (OA). However, the underlying mechanism of protective effect remains unclear. MCP1/CCR2 axis can be stimulated in various periods of OA, and we hypothesize that acupuncture may treat OA by regulating the MCP1/CCR2 axis. This study aimed to explore the effect of acupuncture at points ST35 and ST36 on the effects of hyperalgesia and cartilage in OA rats including the expression of chemokines, nerve growth factor (NGF), and inflammatory-related proteins. OA was induced in male Sprague-Dawley rats by anterior cruciate ligament transection at the right knee. The first acupuncture intervention was performed on the seventh day after surgery and once a day for seven weeks. The knee-pain-related behaviors, histology, and related protein were examined in this study. We have found that electroacupuncture at ST35 and ST36 can significantly alleviate the hyperalgesia and cartilage degeneration as well as reducing nerve sprouting in OA knee joint. Moreover, acupuncture treatment may inhibit the MCP1/CCR2 axis as well as down-regulate inflaming factor and NGF in cartilage and synovial tissue. The data presented here indicate that acupuncture exerts a protective effect against hyperalgesia and cartilage degeneration, and the mechanism might involve in chemokines and NGF pathway.


Asunto(s)
Terapia por Acupuntura , Quimiocina CCL2/metabolismo , Osteoartritis/complicaciones , Dolor/metabolismo , Dolor/prevención & control , Receptores CCR2/metabolismo , Transducción de Señal , Animales , Benzoxazinas/farmacología , Benzoxazinas/uso terapéutico , Cartílago Articular/patología , Citocinas/metabolismo , Ganglios Espinales/patología , Hiperalgesia/prevención & control , Mediadores de Inflamación/metabolismo , Articulación de la Rodilla/patología , Masculino , Factor de Crecimiento Nervioso/metabolismo , Neuronas/patología , Osteoartritis/tratamiento farmacológico , Ratas Sprague-Dawley , Receptor trkA/metabolismo , Compuestos de Espiro/farmacología , Compuestos de Espiro/uso terapéutico , Membrana Sinovial/patología
5.
Mar Drugs ; 17(9)2019 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-31450557

RESUMEN

In this study, we aimed to find chemicals from lower sea animals with defensive effects against human immunodeficiency virus type 1 (HIV-1). A library of marine natural products consisting of 80 compounds was screened for activity against HIV-1 infection using a luciferase-encoding HIV-1 vector. We identified five compounds that decreased luciferase activity in the vector-inoculated cells. In particular, portimine, isolated from the benthic dinoflagellate Vulcanodinium rugosum, exhibited significant anti-HIV-1 activity. Portimine inhibited viral infection with an 50% inhibitory concentration (IC50) value of 4.1 nM and had no cytotoxic effect on the host cells at concentrations less than 200 nM. Portimine also inhibited vesicular stomatitis virus glycoprotein (VSV-G)-pseudotyped HIV-1 vector infection. This result suggested that portimine mainly targeted HIV-1 Gag or Pol protein. To analyse which replication steps portimine affects, luciferase sequences were amplified by semi-quantitative PCR in total DNA. This analysis revealed that portimine inhibits HIV-1 vector infection before or at the reverse transcription step. Portimine has also been shown to have a direct effect on reverse transcriptase using an in vitro reverse transcriptase assay. Portimine efficiently inhibited HIV-1 replication and is a potent lead compound for developing novel therapeutic drugs against HIV-1-induced diseases.


Asunto(s)
Fármacos Anti-VIH/farmacología , Organismos Acuáticos/química , Dinoflagelados/química , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Iminas/farmacología , Compuestos de Espiro/farmacología , Fármacos Anti-VIH/aislamiento & purificación , Fármacos Anti-VIH/uso terapéutico , Evaluación Preclínica de Medicamentos , Células HEK293 , VIH-1/fisiología , Células HeLa , Humanos , Iminas/aislamiento & purificación , Iminas/uso terapéutico , Concentración 50 Inhibidora , Compuestos de Espiro/aislamiento & purificación , Compuestos de Espiro/uso terapéutico , Replicación Viral/efectos de los fármacos
6.
Alcohol Clin Exp Res ; 43(6): 1077-1090, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30908671

RESUMEN

BACKGROUND: Nalfurafine is the first clinically approved kappa-opioid receptor (KOP-r) agonist as an antipruritus drug with few side effects in humans (e.g., sedation, depression, and dysphoria). No study, however, has been done using nalfurafine on alcohol drinking in rodents or humans. METHODS: We investigated whether nalfurafine alone or in combination with mu-opioid receptor (MOP-r) antagonist naltrexone changed excessive alcohol drinking in male and female C57BL/6J (B6) mice subjected to a chronic intermittent-access drinking paradigm (2-bottle choice, 24-hour access every other day) for 3 weeks. Neuronal proopiomelanocortin enhancer (nPE) knockout mice with brain-specific deficiency of beta-endorphin (endogenous ligand of MOP-r) were used as a genetic control for the naltrexone effects. RESULTS: Single administration of nalfurafine decreased alcohol intake and preference in both male and female B6 mice in a dose-dependent manner. Pretreatment with nor-BNI (a selective KOP-r antagonist) blocked the nalfurafine effect on alcohol drinking, indicating a KOP-r-mediated mechanism. Pharmacological effects of a 5-dosing nalfurafine regimen were further evaluated: The repeated nalfurafine administrations decreased alcohol consumption without showing any blunted effects, suggesting nalfurafine did not develop a tolerance after the multidosing regimen tested. Nalfurafine did not produce any sedation (spontaneous locomotor activity), anhedonia-like (sucrose preference test), anxiety-like (elevated plus maze test), or dysphoria-like (conditioned place aversion test) behaviors, suggesting that nalfurafine had few side effects. Investigating synergistic effects between low-dose naltrexone and nalfurafine, we found that single combinations of nalfurafine and naltrexone, at doses lower than individual effective dose, profoundly decreased excessive alcohol intake in both sexes. The effect of nalfurafine on decreasing alcohol consumption was confirmed in nPE-/- mice, suggesting independent mechanisms by which nalfurafine and naltrexone reduced alcohol drinking. CONCLUSION: The clinically utilized KOP-r agonist nalfurafine in combination with low-dose naltrexone has potential in alcoholism treatment.


Asunto(s)
Disuasivos de Alcohol/administración & dosificación , Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Trastornos Relacionados con Alcohol/tratamiento farmacológico , Morfinanos/uso terapéutico , Naltrexona/administración & dosificación , Compuestos de Espiro/uso terapéutico , Animales , Evaluación Preclínica de Medicamentos , Tolerancia a Medicamentos , Femenino , Masculino , Ratones Endogámicos C57BL , Morfinanos/farmacología , Naltrexona/análogos & derivados , Receptores Opioides kappa/agonistas , Sacarina/administración & dosificación , Compuestos de Espiro/farmacología , Sacarosa/administración & dosificación
7.
N Engl J Med ; 379(19): 1835-1845, 2018 11 08.
Artículo en Inglés | MEDLINE | ID: mdl-30403954

RESUMEN

BACKGROUND: Antibiotic-resistant Neisseria gonorrhoeae has prompted the development of new therapies. Zoliflodacin is a new antibiotic that inhibits DNA biosynthesis. In this multicenter, phase 2 trial, zoliflodacin was evaluated for the treatment of uncomplicated gonorrhea. METHODS: We randomly assigned eligible men and women who had signs or symptoms of uncomplicated urogenital gonorrhea or untreated urogenital gonorrhea or who had had sexual contact in the preceding 14 days with a person who had gonorrhea to receive a single oral dose of zoliflodacin (2 g or 3 g) or a single 500-mg intramuscular dose of ceftriaxone in a ratio of approximately 70:70:40. A test of cure occurred within 6±2 days after treatment, followed by a safety visit 31±2 days after treatment. The primary efficacy outcome measure was the proportion of urogenital microbiologic cure in the microbiologic intention-to-treat (micro-ITT) population. RESULTS: From November 2014 through December 2015, a total of 179 participants (167 men and 12 women) were enrolled. Among the 141 participants in the micro-ITT population who could be evaluated, microbiologic cure at urogenital sites was documented in 55 of 57 (96%) who received 2 g of zoliflodacin, 54 of 56 (96%) who received 3 g of zoliflodacin, and 28 of 28 (100%) who received ceftriaxone. All rectal infections were cured in all 5 participants who received 2 g of zoliflodacin and all 7 who received 3 g, and in all 3 participants in the group that received ceftriaxone. Pharyngeal infections were cured in 4 of 8 participants (50%), 9 of 11 participants (82%), and 4 of 4 participants (100%) in the groups that received 2 g of zoliflodacin, 3 g of zoliflodacin, and ceftriaxone, respectively. A total of 84 adverse events were reported: 24 in the group that received 2 g of zoliflodacin, 37 in the group that received 3 g of zoliflodacin, and 23 in the group that received ceftriaxone. According to investigators, a total of 21 adverse events were thought to be related to zoliflodacin, and most such events were gastrointestinal. CONCLUSIONS: The majority of uncomplicated urogenital and rectal gonococcal infections were successfully treated with oral zoliflodacin, but this agent was less efficacious in the treatment of pharyngeal infections. (Funded by the National Institutes of Health and Entasis Therapeutics; ClinicalTrials.gov number, NCT02257918 .).


Asunto(s)
Antibacterianos/administración & dosificación , Barbitúricos/administración & dosificación , Enfermedades Urogenitales Femeninas/tratamiento farmacológico , Gonorrea/tratamiento farmacológico , Enfermedades Urogenitales Masculinas/tratamiento farmacológico , Neisseria gonorrhoeae/aislamiento & purificación , Enfermedades del Recto/tratamiento farmacológico , Compuestos de Espiro/administración & dosificación , Administración Oral , Adolescente , Adulto , Antibacterianos/efectos adversos , Antibacterianos/uso terapéutico , Barbitúricos/efectos adversos , Barbitúricos/uso terapéutico , Ceftriaxona/uso terapéutico , Femenino , Humanos , Inyecciones Intramusculares , Análisis de Intención de Tratar , Isoxazoles , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Morfolinas , Neisseria gonorrhoeae/efectos de los fármacos , Oxazolidinonas , Enfermedades Faríngeas/tratamiento farmacológico , Parejas Sexuales , Compuestos de Espiro/efectos adversos , Compuestos de Espiro/uso terapéutico , Resultado del Tratamiento , Adulto Joven
8.
Expert Opin Pharmacother ; 19(5): 443-450, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29493371

RESUMEN

INTRODUCTION: The prevalence of chronic pruritus (CP) in the general population is high and increases with age. Owing to high rates of comorbidities and polypharmacy in patients aged 65 or older, the clinical management of these patients is challenging. AREAS COVERED: In this review, the authors discuss the available therapy options for patients aged ≥ 65 with CP, including emollients for dry skin, topical therapies, phototherapy and systemic agents for CP of various origins. EXPERT OPINION: For multimorbid patients, topical substances and phototherapy constitute the best initial options. If systemic drugs are needed, the potential side-effects need to be closely monitored. In elderly patients, multiple possible factors for CP, including dermatological and systemic diseases, may be found, complicating the treatment of the underlying cause. In these cases, or when the origin remains unknown, a step-wise symptomatic therapy is recommended. The therapeutic choices should be made on an individual basis after carefully outweighing possible risks and benefits. Novel agents such as neurokinin-1 receptor antagonists and opioid-targeting drugs show promising antipruritic effects on refractory CP and seem to be well tolerated. They may be useful for elderly patients, who cannot tolerate conventional systemic agents.


Asunto(s)
Prurito/terapia , Administración Tópica , Anciano , Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Emolientes/uso terapéutico , Antagonistas de los Receptores Histamínicos/uso terapéutico , Humanos , Inmunosupresores/uso terapéutico , Morfinanos/uso terapéutico , Antagonistas del Receptor de Neuroquinina-1/uso terapéutico , Fototerapia , Prurito/tratamiento farmacológico , Compuestos de Espiro/uso terapéutico
9.
Int J Mol Sci ; 19(1)2017 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-29283381

RESUMEN

A growing body of studies has documented the pathological influence of impaired alternative splicing (AS) events on numerous diseases, including cancer. In addition, the generation of alternatively spliced isoforms is frequently noted to result in drug resistance in many cancer therapies. To gain comprehensive insights into the impacts of AS events on cancer biology and therapeutic developments, this paper highlights recent findings regarding the therapeutic routes of targeting alternative-spliced isoforms and splicing regulators to treatment strategies for distinct cancers.


Asunto(s)
Empalme Alternativo/efectos de los fármacos , Antineoplásicos/uso terapéutico , Proteínas de Neoplasias/antagonistas & inhibidores , Neoplasias/terapia , Factores de Empalme de ARN/antagonistas & inhibidores , ARN Mensajero/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Carcinogénesis/efectos de los fármacos , Carcinogénesis/metabolismo , Carcinogénesis/patología , Caspasa 9/genética , Caspasa 9/metabolismo , Ciclina D1/antagonistas & inhibidores , Ciclina D1/genética , Ciclina D1/metabolismo , Ciclohexilaminas/uso terapéutico , Compuestos Epoxi/uso terapéutico , Humanos , Macrólidos/uso terapéutico , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Oligonucleótidos/genética , Oligonucleótidos/metabolismo , Oligonucleótidos/uso terapéutico , Piranos/uso terapéutico , Factores de Empalme de ARN/genética , Factores de Empalme de ARN/metabolismo , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Compuestos de Espiro/uso terapéutico , Empalmosomas/efectos de los fármacos , Empalmosomas/metabolismo , Proteínas Supresoras de Tumor/antagonistas & inhibidores , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo
10.
Bioorg Med Chem Lett ; 27(7): 1551-1556, 2017 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-28259627

RESUMEN

Herein we report the synthesis of twelve 2,5-substituted 4-(trifluoromethyl)-spirochromeno[4,3-d]pyrimidines (7-10), as well as an evaluation of their analgesic effect in a mouse pain model. The nine new chromeno[4,3-d]pyrimidines (7-9) were synthesized from the cyclocondensation reactions of three 2,2,2-trifluoro-1-(4-methoxyspiro[chromene-2,1'-cycloalkane]-3-yl)ethanones (3) containing 5-, 6- and 7-membered spirocycloalkanes, with some well-known amidine salts (4-6) [NH2CR(NH)]-in which R=Me, Ph, and NH2-at yields of 60-95%. Subsequently, three new 2-(pyrrol-1-yl)-4-(trifluoromethyl)-chromeno[4,3-d]pyrimidines (10) were obtained through a Clauson-Kaas reaction between the respective 2-(amino)-4-(trifluoromethyl)-chromeno[4,3-d]pyrimidines (9) and 2,5-dimethoxy-tetrahydrofuran. The analgesic evaluation showed that these 4-(trifluoromethyl)chromeno[4,3-d]pyrimidines (100mg/kg, p.o.) and Ketoprofen (100mg/kg, p.o.) significantly reduced capsaicin-induced spontaneous nociception. Moreover, the 2-pyrrolyl-spirocyclohexane derivative 10b (100 and 300mg/kg, p.o.) had an anti-allodynic effect comparable to Ketoprofen (100 and 300mg/kg, p.o.) in the arthritic pain model, without causing locomotor alterations in the mice. These results suggest that the compound 10b is a promising molecule for new analgesic drugs in the treatment of pathological pain, such as in arthritis.


Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Benzopiranos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Dolor/tratamiento farmacológico , Pirimidinas/uso terapéutico , Compuestos de Espiro/uso terapéutico , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/síntesis química , Artritis/inducido químicamente , Artritis/tratamiento farmacológico , Artritis/fisiopatología , Benzopiranos/administración & dosificación , Benzopiranos/síntesis química , Capsaicina , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/fisiopatología , Cetoprofeno/administración & dosificación , Cetoprofeno/farmacología , Ratones , Nocicepción/efectos de los fármacos , Dolor/inducido químicamente , Dolor/fisiopatología , Pirimidinas/administración & dosificación , Pirimidinas/síntesis química , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/síntesis química
11.
Artículo en Inglés | MEDLINE | ID: mdl-27872070

RESUMEN

The MIC of an antimalarial drug for a particular infection is the drug level associated with a net parasite multiplication rate of one per asexual cycle. To ensure the cure of malaria, the MIC must be exceeded until all parasites have been eliminated. The development of highly sensitive and accurate PCR quantitation of low-density malaria parasitemia enables the prospective pharmacokinetic-pharmacodynamic (PK-PD) characterization of antimalarial drug effects and now allows identification of the in vivo MIC. An adaptive design and a PK-PD modeling approach were used to determine prospectively the MIC of the new antimalarial cipargamin (KAE609) in adults with uncomplicated Plasmodium falciparum malaria in an open-label, dose-ranging phase 2a study. Vietnamese adults with acute P. falciparum malaria were allocated sequentially to treatment with a single 30-mg (n = 6), 20-mg (n = 5), 10-mg (n = 7), or 15-mg (n = 7) dose of cipargamin. Artemisinin-based combination therapy was given after parasite densities had fallen and then risen as cipargamin levels declined below the MIC but before a return of signs or symptoms. The rates of parasite clearance were dose dependent, with near saturation of the effect being seen at an adult dose of 30 mg. The developed PK-PD model accurately predicted the therapeutic responses in 23/25 patients. The predicted median in vivo MIC was 0.126 ng/ml (range, 0.038 to 0.803 ng/ml). Pharmacometric characterization of the relationship between antimalarial drug concentrations and parasite clearance rates following graded subtherapeutic antimalarial drug dosing is safe and provides a rational framework for dose finding in antimalarial drug development. (This study has been registered at ClinicalTrials.gov under identifier NCT01836458.).


Asunto(s)
Antimaláricos/farmacocinética , Antimaláricos/uso terapéutico , Indoles/farmacocinética , Indoles/uso terapéutico , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/metabolismo , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/uso terapéutico , Adulto , Antimaláricos/efectos adversos , Pueblo Asiatico , Humanos , Indoles/efectos adversos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Compuestos de Espiro/efectos adversos , Adulto Joven
12.
Curr Probl Dermatol ; 50: 133-41, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27578082

RESUMEN

Uremic itch is a frequent and sometimes very tormenting symptom in patients with advanced or end-stage renal failure, with a strong negative impact on the quality of life. According to a representative study, the point prevalence of chronic itch is 25% in hemodialysis patients but may reach more than 50% in single cohorts depending on the country and dialysis efficacy. Not much is known regarding the pathogenesis of uremic itch. Besides parathyroid hormone, histamine, tryptase, and alteration of the calcium-phosphate metabolism have been suspected. More recently, derangements in the opioid system and an inflammatory condition have been investigated as suspected players in the pathogenesis of uremic itch, but remain unproven so far. Treatment of chronic itch in dialysis patients remains difficult. Besides topical application of rehydrating or immunomodulating compounds, such as γ-linolenic acid or tacrolimus treatment with nalfurafine may be helpful. Apart from that, gabapentin and pregabalin are promising drugs to alleviate uremic itch. In many cases, UVB phototherapy is effective in reducing the intensity of itch. When treating patients, one should take into account that most of the drugs available are not licensed for the treatment of itch. Therefore, a deliberate use of therapeutic options aiming for a good risk-benefit relation should be adopted. In very severe and refractory cases, patients suitable for renal transplantation might be switched to 'high urgency' status, as successful renal transplantation cures uremic pruritus in most of the cases.


Asunto(s)
Anticonvulsivantes/uso terapéutico , Inhibidores de la Calcineurina/uso terapéutico , Fallo Renal Crónico/terapia , Prurito/terapia , Diálisis Renal , Terapia Ultravioleta , Uremia/terapia , Terapia por Acupuntura , Aminas/uso terapéutico , Analgésicos Opioides/uso terapéutico , Ácidos Ciclohexanocarboxílicos/uso terapéutico , Gabapentina , Humanos , Fallo Renal Crónico/complicaciones , Morfinanos/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Pregabalina/uso terapéutico , Prurito/etiología , Receptores Opioides kappa/agonistas , Receptores Opioides mu/antagonistas & inhibidores , Compuestos de Espiro/uso terapéutico , Tacrolimus/uso terapéutico , Uremia/complicaciones , Ácido gamma-Aminobutírico/uso terapéutico , Ácido gammalinolénico/uso terapéutico
13.
PLoS One ; 11(7): e0159996, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27467081

RESUMEN

The development of alpha7 nicotinic acetylcholine receptor agonists is considered a promising approach for the treatment of cognitive symptoms in schizophrenia patients. In the present studies we characterized the novel agent, (2R)-N-(6-(1H-imidazol-1-yl)-4-pyrimidinyl)-4'H-spiro[4-azabicyclo[2.2.2]octane-2,5'-[1,3]oxazol]-2'-amine (BMS-933043), in vitro and in rodent models of schizophrenia-like deficits in cognition and sensory processing. BMS-933043 showed potent binding affinity to native rat (Ki = 3.3 nM) and recombinant human alpha7 nicotinic acetylcholine receptors (Ki = 8.1 nM) and agonist activity in a calcium fluorescence assay (EC50 = 23.4 nM) and whole cell voltage clamp electrophysiology (EC50 = 0.14 micromolar (rat) and 0.29 micromolar (human)). BMS-933043 exhibited a partial agonist profile relative to acetylcholine; the relative efficacy for net charge crossing the cell membrane was 67% and 78% at rat and human alpha7 nicotinic acetylcholine receptors respectively. BMS-933043 showed no agonist or antagonist activity at other nicotinic acetylcholine receptor subtypes and was at least 300 fold weaker at binding to and antagonizing human 5-HT3A receptors (Ki = 2,451 nM; IC50 = 8,066 nM). BMS-933043 treatment i) improved 24 hour novel object recognition memory in mice (0.1-10 mg/kg, sc), ii) reversed MK-801-induced deficits in Y maze performance in mice (1-10 mg/kg, sc) and set shift performance in rats (1-10 mg/kg, po) and iii) reduced the number of trials required to complete the extradimensional shift discrimination in neonatal PCP treated rats performing the intra-dimensional/extradimensional set shifting task (0.1-3 mg/kg, po). BMS-933043 also improved auditory gating (0.56-3 mg/kg, sc) and mismatch negativity (0.03-3 mg/kg, sc) in rats treated with S(+)ketamine or neonatal phencyclidine respectively. Given this favorable preclinical profile BMS-933043 was selected for further development to support clinical evaluation in humans.


Asunto(s)
Trastornos del Conocimiento/tratamiento farmacológico , Quinuclidinas/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Compuestos de Espiro/uso terapéutico , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Animales , Trastornos del Conocimiento/fisiopatología , Evaluación Preclínica de Medicamentos , Células HEK293 , Humanos , Masculino , Ratones , Técnicas de Placa-Clamp , Quinuclidinas/farmacología , Ensayo de Unión Radioligante , Ratas , Esquizofrenia/fisiopatología , Compuestos de Espiro/farmacología
14.
Int J Parasitol Drugs Drug Resist ; 6(1): 85-92, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27054067

RESUMEN

We screened a collection of synthetic compounds consisting of natural-product-like substructural motifs to identify a spirocyclic chromane as a novel antiplasmodial pharmacophore using an unbiased cell-based assay. The most active spirocyclic compound UCF 201 exhibits a 50% effective concentration (EC50) of 350 nM against the chloroquine-resistant Dd2 strain and a selectivity over 50 using human liver HepG2 cells. Our analyses of physicochemical properties of UCF 201 showed that it is in compliance with Lipinski's parameters and has an acceptable physicochemical profile. We have performed a limited structure-activity-relationship study with commercially available chromanes preserving the spirocyclic motif. Our evaluation of stage specificities of UCF 201 indicated that the compound is early-acting in blocking parasite development at ring, trophozoite and schizont stages of development as well as merozoite invasion. SPC is an attractive lead candidate scaffold because of its ability to act on all stages of parasite's aexual life cycle unlike current antimalarials.


Asunto(s)
Antimaláricos/química , Antimaláricos/farmacología , Benzofuranos/farmacología , Eritrocitos/parasitología , Malaria/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Compuestos de Espiro/farmacología , Animales , Antimaláricos/síntesis química , Antimaláricos/aislamiento & purificación , Benzofuranos/uso terapéutico , Evaluación Preclínica de Medicamentos , Estadios del Ciclo de Vida/efectos de los fármacos , Malaria/parasitología , Merozoítos/efectos de los fármacos , Merozoítos/crecimiento & desarrollo , Ratones Endogámicos BALB C , Plasmodium berghei , Plasmodium falciparum/crecimiento & desarrollo , Esquizontes/efectos de los fármacos , Esquizontes/crecimiento & desarrollo , Compuestos de Espiro/uso terapéutico , Relación Estructura-Actividad , Trofozoítos/efectos de los fármacos , Trofozoítos/crecimiento & desarrollo
15.
Sci Rep ; 5: 11827, 2015 Jul 14.
Artículo en Inglés | MEDLINE | ID: mdl-26168713

RESUMEN

With the diminishing effectiveness of current antibacterial therapies, it is critically important to discover agents that operate by a mechanism that circumvents existing resistance. ETX0914, the first of a new class of antibacterial agent targeted for the treatment of gonorrhea, operates by a novel mode-of-inhibition against bacterial type II topoisomerases. Incorporating an oxazolidinone on the scaffold mitigated toxicological issues often seen with topoisomerase inhibitors. Organisms resistant to other topoisomerase inhibitors were not cross-resistant with ETX0914 nor were spontaneous resistant mutants to ETX0914 cross-resistant with other topoisomerase inhibitor classes, including the widely used fluoroquinolone class. Preclinical evaluation of ETX0914 pharmacokinetics and pharmacodynamics showed distribution into vascular tissues and efficacy in a murine Staphylococcus aureus infection model that served as a surrogate for predicting efficacious exposures for the treatment of Neisseria gonorrhoeae infections. A wide safety margin to the efficacious exposure in toxicological evaluations supported progression to Phase 1. Dosing ETX0914 in human volunteers showed sufficient exposure and minimal adverse effects to expect a highly efficacious anti-gonorrhea therapy.


Asunto(s)
Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Barbitúricos/farmacología , Barbitúricos/uso terapéutico , Gonorrea/tratamiento farmacológico , Compuestos de Espiro/farmacología , Compuestos de Espiro/uso terapéutico , Inhibidores de Topoisomerasa II/farmacología , Inhibidores de Topoisomerasa II/uso terapéutico , Adulto , Animales , Antibacterianos/química , Barbitúricos/química , ADN-Topoisomerasas de Tipo II/química , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Farmacorresistencia Bacteriana , Femenino , Fluoroquinolonas/farmacología , Gonorrea/microbiología , Haplorrinos , Humanos , Isoxazoles , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Modelos Moleculares , Conformación Molecular , Morfolinas , Mutación , Neisseria gonorrhoeae/efectos de los fármacos , Neisseria gonorrhoeae/genética , Oxazolidinonas , Ratas , Compuestos de Espiro/química , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/efectos de los fármacos , Inhibidores de Topoisomerasa II/química , Adulto Joven
16.
Ann Oncol ; 26(6): 1081-1090, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25755107

RESUMEN

The prevention of chemotherapy-induced nausea and vomiting (CINV) has been revolutionized over the past 25 years. Guideline-based treatment means that vomiting can be prevented in the majority, but not in all patients. Therefore, antiemetic research continues with the goal of optimizing CINV control for all patients. This comprehensive review summarizes the research efforts in this field over the past few years. Emerging from this research are two new antiemetic agents, netupitant/palonosetron, the first antiemetic combination agent and rolapitant, a new NK1RA. In addition, studies have evaluated the benefits of olanzapine and ginger, explored optimal combinations of agents for delayed CINV prevention, confirmed that dexamethasone-sparing regimens are effective, and demonstrated the value of NK1RAs in high-dose chemotherapy settings as well as with certain moderately emetogenic chemotherapies such as carboplatin. Research has also validated the correlation between antiemetic guideline adherence and improved CINV control. Finally, regulatory authorities have utilized extreme caution in retiring some 5-HT3RAs or decreasing their maximum dose.


Asunto(s)
Antieméticos/uso terapéutico , Antineoplásicos/efectos adversos , Descubrimiento de Drogas/tendencias , Náusea/prevención & control , Vómitos/prevención & control , Animales , Combinación de Medicamentos , Adhesión a Directriz , Humanos , Isoquinolinas/uso terapéutico , Náusea/inducido químicamente , Antagonistas del Receptor de Neuroquinina-1/uso terapéutico , Guías de Práctica Clínica como Asunto , Piridinas/uso terapéutico , Quinuclidinas/uso terapéutico , Antagonistas de la Serotonina , Compuestos de Espiro/uso terapéutico , Resultado del Tratamiento , Vómitos/inducido químicamente
17.
Kidney Int ; 87(4): 685-91, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24402092

RESUMEN

Uremic pruritus or chronic kidney disease-associated pruritus (CKD-aP) remains a frequent and compromising symptom in patients with advanced or end-stage renal disease, strongly reducing the patient's quality of life. More than 40% of patients undergoing hemodialysis suffer from chronic pruritus; half of them complain about generalized pruritus. The pathogenesis of CKD-aP remains obscure. Parathormone and histamine as well as calcium and magnesium salts have been suspected as pathogenetic factors. Newer hypotheses are focusing on opioid-receptor derangements and microinflammation as possible causes of CKD-aP, although until now this could not be proven. Pruritus may be extremely difficult to control, as therapeutic options are limited. The most consequential approaches to treatment are: topical treatment with or without anti-inflammatory compounds or systemic treatment with (a) gabapentin, (b) µ-opioid receptor antagonists and κ-agonists, (c) drugs with an anti-inflammatory action, (d) phototherapy, or (e) acupuncture. A stepwise approach is suggested starting with emollients and gabapentin or phototherapy as first-line treatments. In refractory cases, more experimental options as µ-opioid-receptor-antagonists (i.e., naltrexone) or κ-opioid-receptor agonist (nalfurafine) may be chosen. In desperate cases, patients suitable for transplantation might be set on 'high urgency'-status, as successful kidney transplantation will relieve patients from CKD-aP.


Asunto(s)
Prurito/etiología , Prurito/terapia , Insuficiencia Renal Crónica/complicaciones , Uremia/complicaciones , Terapia por Acupuntura , Aminas/uso terapéutico , Antiinflamatorios/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Ácidos Ciclohexanocarboxílicos/uso terapéutico , Gabapentina , Humanos , Morfinanos/uso terapéutico , Naltrexona/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Pentoxifilina/uso terapéutico , Fototerapia , Pregabalina/uso terapéutico , Receptores Opioides kappa/agonistas , Compuestos de Espiro/uso terapéutico , Tacrolimus/uso terapéutico , Talidomida/uso terapéutico , Ácido gamma-Aminobutírico/uso terapéutico , Ácido gammalinolénico/uso terapéutico
18.
Int J Mol Sci ; 15(9): 16911-35, 2014 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-25250910

RESUMEN

Synthesis and anticonvulsant potential of certain new 6-aryl-9-substituted-6,9-diazaspiro[4.5]decane-8,10-diones (6a-l) and 1-aryl-4-substituted-1,4-diazaspiro[5.5] undecane-3,5-diones (6m-x) are reported. The intermediates 1-[(aryl)(cyanomethyl)amino] cycloalkanecarboxamides (3a-f) were prepared via adopting Strecker synthesis on the proper cycloalkanone followed by partial hydrolysis of the obtained nitrile functionality and subsequent N-cyanomethylation. Compounds 3a-f were subjected to complete nitrile hydrolysis to give the respective carboxylic acid derivatives 4a-f which were cyclized under mild conditions to give the spiro compounds 5a-f. Ultimately, compounds 5a-f were alkylated or aralkylated to give the target compounds 6a-i and 6m-u. On the other hand, compounds 6j-l and 6v-x were synthesized from the intermediates 5a-f through alkylation, dehydration and finally tetrazole ring formation. Anticonvulsant screening of the target compounds 6a-x revealed that compound 6g showed an ED50 of 0.0043 mmol/kg in the scPTZ screen, being about 14 and 214 fold more potent than the reference drugs, Phenobarbital (ED50 = 0.06 mmol/kg) and Ethosuximide (ED50 = 0.92 mmol/kg), respectively. Compound 6e exhibited an ED50 of 0.019 mmol/kg, being about 1.8 fold more potent than that of the reference drug, Diphenylhydantoin (ED50 = 0.034 mmol/kg) in the MES screen. Interestingly, all the test compounds 6a-x did not show any minimal motor impairment at the maximum administered dose in the neurotoxicity screen.


Asunto(s)
Anticonvulsivantes/síntesis química , Dicetopiperazinas/síntesis química , Compuestos de Espiro/síntesis química , Animales , Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Convulsivantes/toxicidad , Dicetopiperazinas/química , Dicetopiperazinas/farmacología , Dicetopiperazinas/uso terapéutico , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Electrochoque , Masculino , Ratones , Estructura Molecular , Pentilenotetrazol/toxicidad , Distribución Aleatoria , Prueba de Desempeño de Rotación con Aceleración Constante , Convulsiones/inducido químicamente , Convulsiones/etiología , Convulsiones/prevención & control , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Compuestos de Espiro/uso terapéutico , Relación Estructura-Actividad
19.
Bioorg Med Chem ; 22(15): 4001-9, 2014 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-24997575

RESUMEN

The field of small-molecule inhibitors of protein-protein interactions is rapidly advancing and the specific area of inhibitors of the p53/MDM2 interaction is a prime example. Several groups have published on this topic and multiple compounds are in various stages of clinical development. Building on the strength of the discovery of RG7112, a Nutlin imidazoline-based compound, and RG7388, a pyrrolidine-based compound, we have developed additional scaffolds that provide opportunities for future development. Here, we report the discovery and optimization of a highly potent and selective series of spiroindolinone small-molecule MDM2 inhibitors, culminating in RO8994.


Asunto(s)
Indoles/química , Indolicidinas/química , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Compuestos de Espiro/química , Apoptosis/efectos de los fármacos , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Humanos , Imidazolinas/química , Indoles/uso terapéutico , Indoles/toxicidad , Indolicidinas/uso terapéutico , Indolicidinas/toxicidad , Simulación de Dinámica Molecular , Neoplasias/tratamiento farmacológico , Unión Proteica , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Pirrolidinas/química , Compuestos de Espiro/uso terapéutico , Compuestos de Espiro/toxicidad , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/metabolismo , para-Aminobenzoatos/química
20.
Expert Opin Drug Metab Toxicol ; 10(7): 1051-9, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24785785

RESUMEN

INTRODUCTION: Pharmacologic maintenance of normoglycemia in diabetes cannot prevent the eventual complications mainly due to protein glycation-induced cell death, dysregulated antioxidant defense and signal transduction in affected tissues. The rate-limiting enzyme of this process, aldose reductase, is therefore a pharmacologic target. To date, nine inhibitors of this enzyme have been developed. Ranirestat has completed two Phase III clinical trials. The objective of this evaluation is to summarize and provide expert opinion on the status of ranirestat with an emphasis on its pharmacokinetics in the context of its potential effects to prevent/treat diabetic complications. AREAS COVERED: A qualitative systematic literature search of PubMed through November 2013 using MeSH terms - aldose reductase inhibitors, diabetic neuropathy, AS-3201, ranirestat, diabetic complications and pharmacokinetics/pharmacodynamics - identified relevant publications limited to human and rodent (mouse and rat) and English-language studies. EXPERT OPINION: Ranirestat is a well-tolerated front-line inhibitor. It reproducibly exhibits some degree of measurable objective beneficial outcomes in diabetic neuropathy. It is the furthest advanced in clinical trials with some depth of supporting preclinical data. Trials in subjects with newly diagnosed neuropathy along with the identification of objective biomarkers/measurements of efficacy will be critical in identifying the real value and effect of ranirestat.


Asunto(s)
Neuropatías Diabéticas/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Pirazinas/uso terapéutico , Compuestos de Espiro/uso terapéutico , Aldehído Reductasa/antagonistas & inhibidores , Animales , Biomarcadores/metabolismo , Ensayos Clínicos como Asunto , Neuropatías Diabéticas/fisiopatología , Neuropatías Diabéticas/prevención & control , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Humanos , Ratones , Pirazinas/farmacocinética , Pirazinas/farmacología , Ratas , Reproducibilidad de los Resultados , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA