RESUMEN
A major resistance mechanism in Gram-negative bacteria is the production of ß-lactamase enzymes. Originally recognized for their ability to hydrolyze penicillins, emergent ß-lactamases can now confer resistance to other ß-lactam drugs, including both cephalosporins and carbapenems. The emergence and global spread of ß-lactamase-producing multi-drug-resistant "superbugs" has caused increased alarm within the medical community due to the high mortality rate associated with these difficult-to-treat bacterial infections. To address this unmet medical need, we initiated an iterative program combining medicinal chemistry, structural biology, biochemical testing, and microbiological profiling to identify broad-spectrum inhibitors of both serine- and metallo-ß-lactamase enzymes. Lead optimization, beginning with narrower-spectrum, weakly active compounds, provided 20 (VNRX-5133, taniborbactam), a boronic-acid-containing pan-spectrum ß-lactamase inhibitor. In vitro and in vivo studies demonstrated that 20 restored the activity of ß-lactam antibiotics against carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Enterobacteriaceae. Taniborbactam is the first pan-spectrum ß-lactamase inhibitor to enter clinical development.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Ácidos Borínicos/química , Ácidos Borínicos/farmacología , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Inhibidores de beta-Lactamasas/química , Inhibidores de beta-Lactamasas/farmacología , Animales , Antibacterianos/síntesis química , Antibacterianos/uso terapéutico , Bacterias/efectos de los fármacos , Infecciones Bacterianas/tratamiento farmacológico , Ácidos Borínicos/síntesis química , Ácidos Borínicos/uso terapéutico , Carbapenémicos/farmacología , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/uso terapéutico , Humanos , Ratones , Modelos Moleculares , Resistencia betalactámica , Inhibidores de beta-Lactamasas/síntesis química , Inhibidores de beta-Lactamasas/uso terapéuticoRESUMEN
The healing of Bone tissue consists of a complex process. Hence, we designed our study to evaluate chondrial diseases, which are as they have a very low healing capacity. Seventy two elderly osteoarthritis (OA) and 54-paediatric juvenile idiopathic arthritis (JIA) patients were included. The group was divided as 24 OA patients and 18 JIA patients in each group. Group I received Hyualuronic acid and glucocorticoides. Group II received platelet rich plasma and fibrin glue. Group III received PRP, fibrin glue, and MSC. 40 control patients received only PRP treatment. Out of 72 OA patients 35 (48.6%) male and 37 (51.4%) female with mean age of 48 ± 6.5 years. 64 (88.9%) Patients had pain and swelling. 52 (72.2%) lacked flexibility. 42 (58.3%) had hypertrophy. 28 (38.9%) had less cartilage thickness. 34 (47.2%) were in grade 3, grade 2 has 28 (38.9%) and grade 1 has 10 (13.9%) patients respectively. Among 54 JIA patients 28 (51.9%) male and 26 (48.1%) female patients with mean, age 4.6 ± 3.8 years. 39 (72.2%) had pain and swelling. 32 (59.3%) lacked flexibility. 29 (53.7%) children's had functional disability. Group I patients showed 30% improvement with no statistical significance (P < 0.21). Group II showed 45% improvement with statistical significance (P < 0.01). In Group III 80%, improvement was observed with statistical significance (P < 0.001). In 40 control patients, 60% improvement was observed. In conclusion, use of these MSC, PRP, and PPP are safe and less cost effective for treating OA and JIA.
RESUMEN
A lead optimization campaign in our previously reported sulfamoyl benzamide class of CB(2) agonists was conducted to improve the in vitro metabolic stability profile in this series while retaining high potency and selectivity for the CB(2) receptor. From this study, compound 14, N-(3,4-dimethyl-5-(morpholinosulfonyl)phenyl)-2,2-dimethylbutanamide, was identified as a potent and selective CB(2) agonist exhibiting moderate in vitro metabolic stability and oral bioavailability. Compound 14 demonstrated in vivo efficacy in a rat model of post-surgical pain.
Asunto(s)
Compuestos de Anilina/química , Benzamidas/química , Receptor Cannabinoide CB2/agonistas , Sulfonamidas/química , Compuestos de Anilina/síntesis química , Compuestos de Anilina/farmacocinética , Animales , Benzamidas/síntesis química , Benzamidas/farmacocinética , Humanos , Microsomas Hepáticos/metabolismo , Dolor/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB2/metabolismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacocinéticaRESUMEN
A series of imidazopyrimidine derivatives with the general formula I was synthesized and identified as potent inhibitors of iNOS dimer formation, a prerequisite for proper functioning of the enzyme. Stille and Negishi coupling reactions were used as key steps to form the carbon-carbon bond connecting the imidazopyrimidine core to the central cycloalkenyl, cycloalkyl and phenyl ring templates.
RESUMEN
OBJECTIVE: To investigate the effect of chitosan on the capsule inside the expanded flap. METHODS: The expanders were implanted in animals with the treatment of chitosan(experimental group, n = 15) or without (control group, n = 15). After taking out the expanders, the flap contraction rate was calculated. The samples were observed through HE, Masson dyeing and CD34 immunohistochemical study. The thickness of capsule inside the expanded flap was measured under microscope. The samples were also studied under electron microscope. RESULTS: The thickness of capsule was 516.000 +/- 128.491 microm in the experimental group, and 833.000 +/- 227.379 microm in the control group (P < 0.05). The number of microvessels was 8.200 +/- 2.150 per visual in experimental group, and 7.900 +/- 1.729 per visual in control group (P > 0.05). Under the electron microscope, the rough endoplasmic reticulum (RER) in the capsule in experimental group decreased and enlarged with degranulation. The mitochondria emerged or disappeared. The number of ribosome was reduced. In the control group, the RER enlarged without degranulation, the mitochondria was intact. The number of ribosome was not reduced. CONCLUSIONS: The chitosan can effectively reduce the contraction of expanded flap through collagen secretion of fibroblast, delaying the differentiation from fibroblast to fiber cell, inhibiting thansform from fibroblast to myofibroblast. It has no effect on the microvascular generation and expansion, so the flap blood supply will not be affected with thicker capsule.
Asunto(s)
Quitosano/farmacología , Colgajos Quirúrgicos , Expansión de Tejido , Animales , Quitosano/administración & dosificación , Femenino , Supervivencia de Injerto , Masculino , Conejos , Trasplante de Piel/métodosRESUMEN
Replacement of the phenyl ring in our previous (morpholinomethyl)aniline carboxamide cannabinoid receptor ligands with a pyridine ring led to the discovery of a novel chemical series of CB2 ligands. Compound 3, that is, 2,2-dimethyl-N-(5-methyl-4-(morpholinomethyl)pyridin-2-yl)butanamide was identified as a potent and selective CB2 agonist exhibiting in vivo efficacy after oral administration in a rat model of neuropathic pain.
Asunto(s)
Aminopiridinas/química , Morfolinas/química , Piridinas/química , Receptor Cannabinoide CB2/agonistas , Administración Oral , Aminopiridinas/síntesis química , Aminopiridinas/farmacología , Animales , Perros , Humanos , Masculino , Microsomas Hepáticos , Morfolinas/síntesis química , Morfolinas/farmacología , Dolor/tratamiento farmacológico , Unión Proteica , Piridinas/síntesis química , Piridinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Relación Estructura-ActividadRESUMEN
Selective, nonpeptidic delta opioid receptor agonists have been the subject of great interest as potential novel analgesic agents. The discoveries of BW373U86 (1) and SNC80 (2) contributed to the rapid expansion of research in this field. However, poor drug-like properties and low therapeutic indices have prevented clinical evaluation of these agents. Doses of 1 and 2 similar to those required for analgesic activity produce convulsions in rodents and nonhuman primates. Recently, we described a novel series of potent, selective, and orally bioavailable delta opioid receptor agonists. The lead derivative, ADL5859 (4), is currently in phase II proof-of-concept studies for the management of pain. Further structure activity relationship exploration has led to the discovery of ADL5747 (36), which is approximately 50-fold more potent than 4 in an animal model of inflammatory pain. On the basis of its favorable efficacy, safety, and pharmacokinetic profile, 36 was selected as a clinical candidate for the treatment of pain.
Asunto(s)
Analgésicos/farmacología , Analgésicos/uso terapéutico , Benzamidas/farmacología , Benzamidas/uso terapéutico , Benzopiranos/farmacología , Benzopiranos/uso terapéutico , Dolor/tratamiento farmacológico , Receptores Opioides delta/agonistas , Compuestos de Espiro/farmacología , Compuestos de Espiro/uso terapéutico , Analgésicos/administración & dosificación , Analgésicos/química , Animales , Benzamidas/administración & dosificación , Benzamidas/química , Benzopiranos/administración & dosificación , Benzopiranos/química , Células CHO , Ensayos Clínicos como Asunto , Cricetinae , Cricetulus , Cristalografía por Rayos X , Inhibidores del Citocromo P-450 CYP2D6 , Perros , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Humanos , Hiperalgesia/tratamiento farmacológico , Masculino , Ratas , Ratas Sprague-Dawley , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/químicaRESUMEN
Selective delta opioid receptor agonists are promising potential therapeutic agents for the treatment of various types of pain conditions. A spirocyclic derivative was identified as a promising hit through screening. Subsequent lead optimization identified compound 20 (ADL5859) as a potent, selective, and orally bioavailable delta agonist. Compound 20 was selected as a clinical candidate for the treatment of pain.
Asunto(s)
Analgésicos/administración & dosificación , Benzamidas/administración & dosificación , Benzopiranos/administración & dosificación , Dolor/tratamiento farmacológico , Receptores Opioides delta/agonistas , Administración Oral , Analgésicos/síntesis química , Analgésicos/química , Animales , Benzamidas/síntesis química , Benzamidas/química , Benzopiranos/síntesis química , Benzopiranos/química , Disponibilidad Biológica , Perros , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Humanos , Dosis Máxima Tolerada , Ratones , Estructura Molecular , Actividad Motora/efectos de los fármacos , Dimensión del Dolor/efectos de los fármacos , Ratas , Pruebas de ToxicidadRESUMEN
Nitric oxide (NO), a mediator of various physiological and pathophysiological processes, is synthesized by three isozymes of nitric oxide synthase (NOS). Potential candidate clinical drugs should be devoid of inhibitory activity against endothelial NOS (eNOS), since eNOS plays an important role in maintaining normal blood pressure and flow. A new series of aminopiperidines as potent inhibitors of iNOS were identified from a HTS lead. From this study, we identified compound 33 as a potent iNOS inhibitor, with >25-fold selectivity over eNOS and 16-fold selectivity over nNOS.
Asunto(s)
Aminas/síntesis química , Aminas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Piperidinas/síntesis química , Piperidinas/farmacología , Aminas/química , Sitios de Unión , Diseño de Fármacos , Inhibidores Enzimáticos/química , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo I/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III/metabolismo , Piperidinas/química , Relación Estructura-ActividadRESUMEN
A novel series of malonamide derivatives was synthesized. These amides were shown to be potent and selective kappa opioid receptor agonists.
Asunto(s)
Química Farmacéutica/métodos , Malonatos/síntesis química , Malonatos/farmacología , Receptores Opioides kappa/antagonistas & inhibidores , Citocromo P-450 CYP2D6/química , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Cinética , Malonatos/química , Modelos Químicos , Conformación MolecularRESUMEN
A novel series of phenylamino acetamide derivatives was synthesized. These amides were shown to be potent and selective kappa opioid receptor agonists.
Asunto(s)
Acetamidas/química , Analgésicos Opioides/química , Compuestos de Anilina/química , Receptores Opioides kappa/agonistas , Analgésicos Opioides/farmacología , Animales , Humanos , Relación Estructura-ActividadRESUMEN
Two novel chemical classes of kappa opioid receptor agonists, chroman-2-carboxamide derivatives and 2,3-dihydrobenzofuran-2-carboxamide derivatives, were synthesized. These agents exhibited high and selective affinity for the kappa opioid receptor.
Asunto(s)
Amidas/farmacología , Analgésicos Opioides/química , Analgésicos Opioides/farmacología , Cromanos/farmacología , Receptores Opioides kappa/agonistas , Amidas/síntesis química , Amidas/química , Animales , Benzofuranos/química , Cromanos/síntesis química , Cromanos/química , HumanosRESUMEN
We report the synthesis and radioligand binding analysis of a series of naphthalenic melatonin receptor ligands, N-[2-(7-alkoxy-2-methoxy-1-naphthyl)ethyl]propionamide. This series of ligands exhibits subpicomolar binding affinity to both MT1 and MT2 melatonin receptors expressed in chinese hamster ovary (CHO) cells.