RESUMEN
Leucettinibs are substituted 2-aminoimidazolin-4-ones (inspired by the marine sponge natural product Leucettamine B) developed as pharmacological inhibitors of DYRK1A (dual-specificity, tyrosine phosphorylation-regulated kinase 1A), a therapeutic target for indications such as Down syndrome and Alzheimer's disease. Leucettinib-21 was selected as a drug candidate following extensive structure/activity studies and multiparametric evaluations. We here report its physicochemical properties (X-ray powder diffraction, differential scanning calorimetry, stability, solubility, crystal structure) and drug-like profile. Leucettinib-21's selectivity (analyzed by radiometric, fluorescence, interaction, thermal shift, residence time assays) reveals DYRK1A as the first target but also some "off-targets" which may contribute to the drug's biological effects. Leucettinib-21 was cocrystallized with CLK1 and modeled in the DYRK1A structure. Leucettinib-21 inhibits DYRK1A in cells (demonstrated by direct catalytic activity and phosphorylation levels of Thr286-cyclin D1 or Thr212-Tau). Leucettinib-21 corrects memory disorders in the Down syndrome mouse model Ts65Dn and is now entering safety/tolerance phase 1 clinical trials.
Asunto(s)
Enfermedad de Alzheimer , Síndrome de Down , Animales , Ratones , Enfermedad de Alzheimer/tratamiento farmacológico , Síndrome de Down/tratamiento farmacológico , Fosforilación , Proteínas Serina-Treonina Quinasas , Proteínas Tirosina Quinasas , Imidazolidinas/química , Imidazolidinas/farmacologíaRESUMEN
Dual-specificity, tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) recently attracted attention due to their central involvement in various pathologies. We here describe a family of DYRK/CLK inhibitors derived from Leucettines and the marine natural product Leucettamine B. Forty-five N2-functionalized 2-aminoimidazolin-4-ones bearing a fused [6 + 5]-heteroarylmethylene were synthesized. Benzothiazol-6-ylmethylene was selected as the most potent residue among 15 different heteroarylmethylenes. 186 N2-substituted 2-aminoimidazolin-4-ones bearing a benzothiazol-6-ylmethylene, collectively named Leucettinibs, were synthesized and extensively characterized. Subnanomolar IC50 (0.5-20 nM on DYRK1A) inhibitors were identified and one Leucettinib was modeled in DYRK1A and co-crystallized with CLK1 and the weaker inhibited off-target CSNK2A1. Kinase-inactive isomers of Leucettinibs (>3-10 µM on DYRK1A), named iso-Leucettinibs, were synthesized and characterized as suitable negative control compounds for functional experiments. Leucettinibs, but not iso-Leucettinibs, inhibit the phosphorylation of DYRK1A substrates in cells. Leucettinibs provide new research tools and potential leads for further optimization toward therapeutic drug candidates.
Asunto(s)
Imidazoles , Poríferos , Animales , Fosforilación , Imidazoles/química , Poríferos/química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/químicaRESUMEN
Dual-specificity, tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) play a large variety of cellular functions and are involved in several diseases (cognitive disorders, diabetes, cancers, etc.). There is, thus, growing interest in pharmacological inhibitors as chemical probes and potential drug candidates. This study presents an unbiased evaluation of the kinase inhibitory activity of a library of 56 reported DYRK/CLK inhibitors on the basis of comparative, side-by-side, catalytic activity assays on a panel of 12 recombinant human kinases, enzyme kinetics (residence time and Kd), in-cell inhibition of Thr-212-Tau phosphorylation, and cytotoxicity. The 26 most active inhibitors were modeled in the crystal structure of DYRK1A. The results show a rather large diversity of potencies and selectivities among the reported inhibitors and emphasize the difficulties to avoid "off-targets" in this area of the kinome. The use of a panel of DYRKs/CLKs inhibitors is suggested to analyze the functions of these kinases in cellular processes.
Asunto(s)
Proteínas Quinasas , Procesamiento Proteico-Postraduccional , Humanos , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/químicaRESUMEN
Herein, we report the discovery of a first-in-class chemotype 2-(alkylsulfonamido)thiazol-4-yl)acetamides that act as pan-selective inhibitors of cytidine 5'-triphosphate synthetase (CTPS1/2), critical enzymes in the de novo pyrimidine synthesis pathway. Weak inhibitors identified from a high-throughput screening of 240K compounds have been optimized to a potent, orally active agent, compound 27, which has shown significant pharmacological responses at 10 mg/kg dose BID in a well-established animal model of inflammation.
Asunto(s)
Ligasas de Carbono-Nitrógeno , Inhibidores Enzimáticos , Animales , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Ligasas de Carbono-Nitrógeno/metabolismo , Proliferación Celular , Ensayos Analíticos de Alto RendimientoRESUMEN
PURPOSE: To present the experience and efficacy of Robotic Partial Nephrectomy (RPN) for the management of renal angiomyolipomas (AMLs) with regard to renal function preservation and perioperative outcomes. PATIENTS AND METHODS: We retrospectively searched our RPN database for pathologically confirmed renal AML patients between 2006 and 2014. Clinical presentation, perioperative complications, and postoperative outcomes of the patients were analyzed. Preoperative imaging findings were reviewed to examine their ability to predict pathology of AML. RESULTS: From 1005 RPN performed in our center during the study period, 53 patients met our inclusion criteria. The mean age at presentation was 54.1 (± 13) years, and 42 (79.2%) patients were female. Median tumor size was 2.8 (interquartile range [IQR], 1.8-4.6) cm. The indication for RPN was suspicious radiologic features for malignancy in 42 (79.2%) patients and acute retroperitoneal hemorrhage risk and pain in 11 (20.8%) patients who were found to have AML according to preoperative imaging. Mean estimated blood loss was 198 (± 194) mL, and 5 (9.4%) patients required blood transfusion. Postoperative complications occurred in 8 (15%) patients. Median estimated glomerular filtration rate within the latest follow-up was 86.9 (IQR, 69.7-100.1) mL/minute/1.73 m(2) with a median of 91% (IQR, 80.4-103) preservation. None of patients developed urinary fistula or pseudoaneurysm requiring second intervention. No local recurrences occurred with a median follow-up of 7 (IQR, 1-17) months. CONCLUSION: Given the low complication rate and preservation of renal function after RPN for AML, it can be considered a reliable method for AML treatment. The majority of AMLs were not suspected based on preoperative imaging. Further diagnostic methods are needed to differentiate benign from malignant lesions.
Asunto(s)
Angiomiolipoma/cirugía , Neoplasias Renales/cirugía , Recurrencia Local de Neoplasia , Nefrectomía/métodos , Procedimientos Quirúrgicos Robotizados/métodos , Adulto , Anciano , Angiomiolipoma/complicaciones , Angiomiolipoma/diagnóstico , Femenino , Hemorragia/etiología , Humanos , Neoplasias Renales/complicaciones , Neoplasias Renales/diagnóstico , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias , Espacio Retroperitoneal , Estudios Retrospectivos , Carga TumoralRESUMEN
Lead compounds 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-benzamide (1), tetrahydro-pyran-4-carboxylic acid [((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-amide (2), and 3,5-dimethyl-isoxazole-4-carboxylic acid [((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-amide (3) discovered in our laboratory, displayed high histamine H3 receptor (H3R) affinity, good selectivity and weak human Ether-à-go-go-Related Gene (hERG) channel affinity with desirable overall physico-chemical and pharmacokinetic (PK) profiles. Herein, we describe the design and synthesis of a novel series of H3R antagonists utilizing a scaffold hopping strategy. Further structure-activity relationship (SAR) studies of the series culminated in the identification of ((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-naphthalene-2-carboxylic acid (tetrahydro-pyran-4-yl)-amide (4c) and -[4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-N-(tetrahydro-pyran-4-yl)-acetamide (4d), which exhibited good H3R affinity in vitro, good selectivity, and desirable PK properties. Compounds 4c and 4d were also assessed in cardiac safety experiments. In particular, the effects of the compounds on action potentials recorded from ventricular myocytes isolated from guinea pigs were used to screen compounds that not only displayed a low affinity towards hERG channel, but also had lower interference with other cardiac ion channels. Compound 4c did not alter the major parameters in this model system at ⩽10 µM, and no significant induction of any major haemodynamic effect when intravenously administered at 3mg/kg dose to anaesthetized mongrel dogs. Compound 4c is a new promising lead as orally potent and selective H3R antagonist belonging to a distinct structural class.
Asunto(s)
Antagonistas de los Receptores Histamínicos H3/química , Antagonistas de los Receptores Histamínicos H3/síntesis química , Animales , Células CHO , Cricetulus , Perros , Diseño de Fármacos , Femenino , Cobayas , Antagonistas de los Receptores Histamínicos H3/farmacología , Humanos , Masculino , Técnicas de Placa-Clamp , Estereoisomerismo , Relación Estructura-Actividad , Transactivadores/metabolismo , Regulador Transcripcional ERGRESUMEN
Monoacylglycerol lipase (MAGL) represents a primary degradation enzyme of the endogenous cannabinoid (eCB), 2-arachidonoyglycerol (2-AG). This study reports a potent covalent MAGL inhibitor, SAR127303. The compound behaves as a selective and competitive inhibitor of mouse and human MAGL, which potently elevates hippocampal levels of 2-AG in mice. In vivo, SAR127303 produces antinociceptive effects in assays of inflammatory and visceral pain. In addition, the drug alters learning performance in several assays related to episodic, working and spatial memory. Moreover, long term potentiation (LTP) of CA1 synaptic transmission and acetylcholine release in the hippocampus, two hallmarks of memory function, are both decreased by SAR127303. Although inactive in acute seizure tests, repeated administration of SAR127303 delays the acquisition and decreases kindled seizures in mice, indicating that the drug slows down epileptogenesis, a finding deserving further investigation to evaluate the potential of MAGL inhibitors as antiepileptics. However, the observation that 2-AG hydrolysis blockade alters learning and memory performance, suggests that such drugs may have limited value as therapeutic agents.
Asunto(s)
Analgésicos/farmacología , Ácidos Araquidónicos/metabolismo , Carbamatos/farmacología , Endocannabinoides/metabolismo , Glicéridos/metabolismo , Aprendizaje/efectos de los fármacos , Memoria a Corto Plazo/efectos de los fármacos , Monoacilglicerol Lipasas/metabolismo , Sulfonamidas/farmacología , Acetilcolina/metabolismo , Administración Oral , Analgésicos/química , Analgésicos/uso terapéutico , Animales , Ácidos Araquidónicos/química , Sitios de Unión , Encéfalo/metabolismo , Antagonistas de Receptores de Cannabinoides/farmacología , Carbamatos/química , Carbamatos/uso terapéutico , Cromatografía Líquida de Alta Presión , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Estimulación Eléctrica , Endocannabinoides/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Glicéridos/química , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Humanos , Hidrólisis , Técnicas In Vitro , Potenciación a Largo Plazo/efectos de los fármacos , Espectrometría de Masas , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Monoacilglicerol Lipasas/antagonistas & inhibidores , Dolor/tratamiento farmacológico , Dolor/patología , Piperidinas/farmacología , Estructura Terciaria de Proteína , Pirazoles/farmacología , Rimonabant , Convulsiones/tratamiento farmacológico , Convulsiones/patología , Sulfonamidas/química , Sulfonamidas/uso terapéuticoRESUMEN
Purpose To investigate risk factors for urine leak in patients undergoing minimally invasive partial nephrectomy (MIPN) and to determine the role of intraoperative ureteral catheterization in preventing this postoperative complication. Materials and Methods MIPN procedures done from September 1999 to July 2012 at our Center were reviewed from our IRB-approved database. Patient and tumor characteristics, operative techniques and outcomes were analyzed. Patients with evidence of urine leak were identified. Outcomes were compared between patients with preoperative ureteral catheterization (C-group) and those without (NC-group). Univariable and multivariable analyses were performed to identify factors predicting postoperative urine leak. Results A total of 1,019 cases were included (452 robotic partial nephrectomy cases and 567 laparoscopic partial nephrectomy cases). Five hundred twenty eight patients (51.8%) were in the C-group, whereas 491 of them (48.2%) in the NC-group. Urine leak occurred in 31(3%) cases, 4.6% in the C-group and 1.4% in the NC-group (p<0.001). Tumors in NC-group had significantly higher RENAL score, shorter operative and warm ischemic times. On multivariable analysis, tumor proximity to collecting system (OR=9.2; p<0.01), surgeon’s early operative experience (OR=7.8; p<0.01) and preoperative moderate to severe CKD (OR=3.1; p<0.01) significantly increased the odds of the occurrence of a postoperative urine leak. Conclusion Clinically significant urine leak after MIPN in a high volume institution setting is uncommon. This event is more likely to occur in cases of renal masses that are close to the collecting system, in patients with preoperative CKD and when operating surgeon is still in the learning curve for the procedure. Our findings suggest that routine intraoperative ureteral catheterization during MIPN does not reduce the probability of postoperative urine leak. In addition, it adds to the overall ...
Asunto(s)
Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nefrectomía/efectos adversos , Cateterismo Urinario/métodos , Incontinencia Urinaria/etiología , Incontinencia Urinaria/prevención & control , Tasa de Filtración Glomerular , Cuidados Intraoperatorios , Análisis Multivariante , Procedimientos Quirúrgicos Mínimamente Invasivos/efectos adversos , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Nefrectomía/métodos , Tempo Operativo , Reproducibilidad de los Resultados , Factores de Riesgo , Insuficiencia Renal Crónica/cirugía , Índice de Severidad de la Enfermedad , Estadísticas no Paramétricas , Factores de Tiempo , Resultado del TratamientoRESUMEN
The aim of this study is to examine the role of robotic partial nephrectomy (RPN) in the management of caliceal diverticula by assessing our single-center outcomes. Between July 2007 and July 2013, 7 of 670 patients underwent RPN procedures as a reason of caliceal diverticula. The indications for RPN in all cases were recurrent urinary tract infection and pain attributed to the diverticulum in addition to failed management by endourologic or extracorporeal shockwave lithotripsy (SWL) treatments. One patient with a calcified diverticulum and another with an unsuccessful SWL treatment underwent RPN without further endourologic intervention. The other five patients had a history of unsuccessful percutaneous nephrolithotomy (one case), ureteroscopy (URS) (two cases), and a combination of SWL+URS (two cases). No intraoperative or postoperative complications were observed. No patient was readmitted postoperatively. Unique features of the robotic platform facilitate the excision of diverticulum and subsequent kidney reconstruction for this benign, but complex pathology.
Asunto(s)
Divertículo/cirugía , Cálices Renales/cirugía , Enfermedades Renales/cirugía , Nefrectomía/métodos , Robótica/métodos , Adolescente , Adulto , Divertículo/complicaciones , Femenino , Humanos , Cálculos Renales/cirugía , Litotricia/métodos , Masculino , Persona de Mediana Edad , Nefrostomía Percutánea , Complicaciones Posoperatorias , Ureteroscopía/métodos , Infecciones Urinarias/etiología , Adulto JovenRESUMEN
PURPOSE: To investigate risk factors for urine leak in patients undergoing minimally invasive partial nephrectomy (MIPN) and to determine the role of intraoperative ureteral catheterization in preventing this postoperative complication. MATERIALS AND METHODS: MIPN procedures done from September 1999 to July 2012 at our Center were reviewed from our IRB-approved database. Patient and tumor characteristics, operative techniques and outcomes were analyzed. Patients with evidence of urine leak were identified. Outcomes were compared between patients with preoperative ureteral catheterization (C-group) and those without (NC-group). Univariable and multivariable analyses were performed to identify factors predicting postoperative urine leak. RESULTS: A total of 1,019 cases were included (452 robotic partial nephrectomy cases and 567 laparoscopic partial nephrectomy cases). Five hundred twenty eight patients (51.8%) were in the C-group, whereas 491 of them (48.2%) in the NC-group. Urine leak occurred in 31(3%) cases, 4.6% in the C-group and 1.4% in the NC-group (p<0.001). Tumors in NC-group had significantly higher RENAL score, shorter operative and warm ischemic times. On multivariable analysis, tumor proximity to collecting system (OR=9.2; p<0.01), surgeon's early operative experience (OR=7.8; p<0.01) and preoperative moderate to severe CKD (OR=3.1; p<0.01) significantly increased the odds of the occurrence of a postoperative urine leak. CONCLUSION: Clinically significant urine leak after MIPN in a high volume institution setting is uncommon. This event is more likely to occur in cases of renal masses that are close to the collecting system, in patients with preoperative CKD and when operating surgeon is still in the learning curve for the procedure. Our findings suggest that routine intraoperative ureteral catheterization during MIPN does not reduce the probability of postoperative urine leak. In addition, it adds to the overall operative time.
Asunto(s)
Nefrectomía/efectos adversos , Cateterismo Urinario/métodos , Incontinencia Urinaria/etiología , Incontinencia Urinaria/prevención & control , Anciano , Femenino , Tasa de Filtración Glomerular , Humanos , Cuidados Intraoperatorios , Masculino , Persona de Mediana Edad , Procedimientos Quirúrgicos Mínimamente Invasivos/efectos adversos , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Análisis Multivariante , Nefrectomía/métodos , Tempo Operativo , Insuficiencia Renal Crónica/cirugía , Reproducibilidad de los Resultados , Factores de Riesgo , Índice de Severidad de la Enfermedad , Estadísticas no Paramétricas , Factores de Tiempo , Resultado del TratamientoRESUMEN
Previous studies have shown that compound 1 displayed high affinity towards histamine H3 receptor (H3R), (human (h-H3R), K(i)=8.6 nM, rhesus monkey (rh-H3R), K(i)=1.2 nM, and rat (r-H3R), K(i)=16.5 nM), but exhibited high affinity for hERG channel. Herein, we report the discovery of a novel, potent, and highly selective H3R antagonist/inverse agonist 5a(SS) (SAR110068) with acceptable hERG channel selectivity and desirable pharmacological and pharmacokinetic properties through lead optimization sequence. The significant awakening effects of 5a(SS) on sleep-wake cycles studied by using EEG recording in rats during their light phase support its potential therapeutic utility in human sleep-wake disorders.
Asunto(s)
Antagonistas de los Receptores Histamínicos H3/farmacología , Piranos/farmacología , Pirrolidinas/farmacología , Trastornos del Sueño del Ritmo Circadiano/tratamiento farmacológico , Administración Oral , Animales , Perros , Estabilidad de Medicamentos , Cobayas , Haplorrinos , Antagonistas de los Receptores Histamínicos H3/química , Antagonistas de los Receptores Histamínicos H3/farmacocinética , Humanos , Masculino , Ratones , Piranos/química , Piranos/farmacocinética , Pirrolidinas/química , Pirrolidinas/farmacocinética , Conejos , Ratas , Ratas Sprague-Dawley , Receptores Histamínicos H3/química , Receptores Histamínicos H3/metabolismo , Ovinos , Trastornos del Sueño del Ritmo Circadiano/metabolismo , Especificidad por SustratoRESUMEN
Lead optimization guided by histamine H3 receptor (H3R) affinity and calculated physico-chemical properties enabled simultaneous improvement in potency and PK properties leading to the identification of a potent, selective, devoid of hERG issues, orally bioavailable, and CNS penetrable H3R antagonist/inverse agonist 3h. The compound was active in forced-swimming tests suggesting its potential therapeutic utility as an anti-depressive agent. This Letter further includes its cardiovascular and neuropsychological/behavioral safety assessments.
Asunto(s)
Amidas/química , Antidepresivos/química , Antagonistas de los Receptores Histamínicos/química , Pirrolidinas/química , Amidas/farmacocinética , Amidas/farmacología , Animales , Antidepresivos/farmacocinética , Antidepresivos/farmacología , Células CHO , Cricetulus , Antagonistas de los Receptores Histamínicos/farmacocinética , Antagonistas de los Receptores Histamínicos/farmacología , Humanos , Cinética , Masculino , Ratones , Pirrolidinas/farmacocinética , Pirrolidinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Histamínicos H3/química , Receptores Histamínicos H3/metabolismoRESUMEN
This Letter describes the asymmetric synthesis of the four stereoisomers (8a-8d) of a potent and highly selective histamine H3 receptor (H3R) antagonist, 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl[1,3']bipyrrolidinyl-1'-yl) phenyl]benzamide (1). The physico-chemical properties, in vitro H3R affinities and ADME of 8a-8d were determined. Stereoisomer 8c (2S,3'S) displayed superior in vitro H3R affinity over other three stereoisomers and was selected for further profiling in in vivo PK and drug safety. Compound 8c exhibited excellent PK properties with high exposure, desired brain to plasma ratio and reasonable brain half life. However, all stereoisomers showed similar unwanted hERG affinities.
Asunto(s)
Benzamidas/química , Benzamidas/síntesis química , Antagonistas de los Receptores Histamínicos/síntesis química , Pirrolidinas/síntesis química , Receptores Histamínicos H3/química , Animales , Benzamidas/farmacocinética , Encéfalo/metabolismo , Semivida , Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/farmacocinética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Microsomas Hepáticos/metabolismo , Pirrolidinas/química , Pirrolidinas/farmacocinética , Ratas , Receptores Histamínicos H3/metabolismo , EstereoisomerismoRESUMEN
A series of structurally novel aryl ureas was derived from optimization of the HTS lead as selective histamine H3 receptor (H3R) antagonists. The SAR was explored and the data obtained set up the starting point and foundation for further optimization. The most potent tool compounds, as exemplified by compounds 2l, 5b, 5d, and 5e, displayed antagonism potencies in the subnanomolar range in in vitro human-H3R FLIPR assays and rhesus monkey H3R binding assays.
Asunto(s)
Amidas/química , Antagonistas de los Receptores Histamínicos H3/química , Receptores Histamínicos H3/química , Urea/química , Amidas/metabolismo , Amidas/uso terapéutico , Animales , Evaluación Preclínica de Medicamentos , Células HEK293 , Antagonistas de los Receptores Histamínicos H3/metabolismo , Antagonistas de los Receptores Histamínicos H3/uso terapéutico , Humanos , Macaca mulatta , Obesidad/tratamiento farmacológico , Unión Proteica , Ratas , Receptores Histamínicos H3/genética , Receptores Histamínicos H3/metabolismo , Relación Estructura-Actividad , Urea/metabolismo , Urea/uso terapéuticoRESUMEN
A novel series of histamine H3 receptor (H3R) antagonists was derived from an arylurea lead series (1) via bioisosteric replacement of the urea functionality by an amide linkage. The arylamide series was optimized through SAR studies by a broad variation of substituents in the left-hand side benzoyl residue (analogs 2a-2ag) or replacement of the benzoyl moiety by heteroarylcarbonyl residues (analogs 5a-5n). Compounds 2p and 2q were identified within the series as potent and selective H3R antagonists/inverse agonists with acceptable overall profile. Compound 2q was orally active in food intake inhibition in diet-induced obese (DIO) mice. Compound 2q represents a novel H3R antagonist template with improved in vitro potency and oral efficacy and has its merits as a new lead for further optimization.
Asunto(s)
Amidas/química , Benzamidas/química , Antagonistas de los Receptores Histamínicos H3/química , Pirrolidinas/química , Receptores Histamínicos H3/química , Urea/química , Administración Oral , Amidas/metabolismo , Amidas/uso terapéutico , Animales , Benzamidas/metabolismo , Benzamidas/uso terapéutico , Células CACO-2 , Evaluación Preclínica de Medicamentos , Agonismo Inverso de Drogas , Antagonistas de los Receptores Histamínicos H3/metabolismo , Antagonistas de los Receptores Histamínicos H3/uso terapéutico , Humanos , Ratones , Microsomas/metabolismo , Obesidad/tratamiento farmacológico , Unión Proteica , Pirrolidinas/metabolismo , Pirrolidinas/uso terapéutico , Ratas , Receptores Histamínicos H3/genética , Receptores Histamínicos H3/metabolismo , Relación Estructura-Actividad , Urea/metabolismo , Urea/uso terapéuticoRESUMEN
As the replacement of a hydrogen atom by a fluorine atom in a compound can have an important impact on its biological properties, the development of methods allowing the introduction of a fluorine atom is of great importance. The scope and limitations of the ring expansion of cyclic 2-hydroxymethyl amines induced by diethylaminosulfur trifluoride (DAST) to produce cyclic ß-fluoro amines was studied as well as the enantioselectivity of the process.
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Aminas/síntesis química , Amino Alcoholes/química , Dietilaminas/química , Flúor/química , Aminas/química , Ciclización , Estructura Molecular , EstereoisomerismoRESUMEN
An in-depth study of the cobalt-catalyzed [2+2+2] cycloaddition between yne-ynamides and nitriles to afford aminopyridines has been carried out. About 30 nitriles exhibiting a broad range of steric demand and electronic properties have been evaluated, some of which open new perspectives in metal-catalyzed arene formation. In particular, the use of [CpCo(CO)(dmfu)] (dmfu=dimethyl fumarate) as a precatalyst made possible the incorporation of electron-deficient nitriles into the pyridine core. Modification of the substitution pattern at the yne-ynamide allows the regioselectivity to be switched toward 3- or 4-aminopyridines. Application of this synthetic methodology to the construction of the aminopyridone framework using a yne-ynamide and an isocyanate was also briefly examined. DFT computations suggest that 3-aminopyridines are formed by formal [4+2] cycloaddition between the nitrile and the intermediate cobaltacyclopentadiene, whereas 4-aminopyridines arise from an insertion pathway.
Asunto(s)
Alquinos/química , Amidas/química , Aminopiridinas/síntesis química , Cobalto/química , Nitrilos/química , Piridonas/síntesis química , Aminopiridinas/química , Catálisis , Ciclización , Estructura Molecular , Piridonas/química , EstereoisomerismoRESUMEN
UNLABELLED: What's known on the subject? and What does the study add? Single port transvesical enucleation of the prostate (STEP) performed through a solitary suprapubic incision using a single access port inserted directly into the bladder has been demonstrated to be technically feasible but still challenging.3. Despite being feasible and providing adequate relief of bladder outlet obstruction, robotic STEP carries a high risk of complications. Further evolution of the technique is likely to be strictly dependent on the development of instrumentation. OBJECTIVE: To report our initial experience with a novel robot assisted single port procedure for the management of benign prostatic hyperplasia (BPH). METHODS: Between March 2009 and July 2010, nine patients with symptomatic BPH were scheduled for robotic single port suprapubic transvesical enucleation of the prostate (R-STEP). Prior to intervention, all were submitted to preoperative transrectal ultrasound of the prostate and uroflowmetry. The surgical procedure included an initial transurethral incision of the prostatic apex. With the patient in the supine position, an approximate 3 cm lower midline incision was made. A cystotomy was created and a GelPort(®) laparoscopic system positioned in the bladder. The da Vinci S™ robotic operating system was docked through the GelPort(®) platform and enucleation was performed. Perioperative outcomes and short-term postoperative functional outcomes were assessed. Intra-operative and postoperative complications, graded according to the Dindo-Clavien system, were recorded. RESULTS: One patient was excluded from the analysis as the procedure was aborted and converted to open simple prostatectomy. Median operative time was 3.9 h. Median visual analogue pain scale on discharge was 2. Estimated blood loss was 425 mL. Two patients required intra-operative blood transfusion. Postoperatively, two patients developed clot retention and required evacuation and fulguration (grade IIIb), one of them had a deep vein thrombosis (grade II) and a urinary tract infection (grade II). One patient was admitted to the intensive care unit after a myocardial infarction (grade IVa). All patients were discharged after a median of 4.5 days. There was almost three and four times postoperative improvement in both median maximum flow (Qmax) and average flow (Qave) rates, respectively. CONCLUSION: The first series of R-STEP is reported herein. Despite being feasible and providing adequate relief of bladder outlet obstruction, the procedure carries a high risk of complications. Further evolution of the technique is likely to be strictly dependent on the development of instrumentation. Thus, its role in the surgical armamentarium of BPH remains to be determined.