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Discovery and optimization of a series of carbazole ureas as NPY5 antagonists for the treatment of obesity.
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The hypothesis that antagonists of the neuropeptide Y5 receptor would provide safe and effective appetite suppressants for the treatment of obesity has prompted vigorous research to identify suitable compounds. We discovered a series of acylated aminocarbazole derivatives (e.g., 3a) that are potent
Ammonium uptake and urea production in hepatocytes from lean and obese Zucker rats.
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The metabolic differences in vitro between genetic and dietary obese rats in the uptake of ammonium and amino acids by the liver and their use for ureogenesis have been assayed using hepatocytes isolated from Lean, Obese Zucker (Genetic obese) rats and Dietary obese rats. The hepatocytes of genetic
Biaryl ureas as potent and orally efficacious melanin concentrating hormone receptor 1 antagonists for the treatment of obesity.
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Herein, we report a small molecule MCH-R1 antagonist which demonstrates oral efficacy in chronic rodent models. Substituted phenyl biaryl urea derivatives were synthesized and evaluated as MCH-R1 antagonists for the treatment of obesity. The structure-activity relationship studies in this series
Discovery of aryl ureas and aryl amides as potent and selective histamine H3 receptor antagonists for the treatment of obesity (part II).
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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
The effect of rate and extent of weight loss on urea salvage in obese male subjects.
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It is well established that in human subjects a proportion of urea production undergoes hydrolysis in the gastrointestinal tract with release of N potentially available for amino acid synthesis. Previous studies have suggested adaptive changes in urea kinetics, with more urea-N retained within the
Biosynthesis of hippurate, urea and pyrimidines in the fatty liver: studies with rats fed orotic acid or a diet deficient in choline and inositol, and with genetically obese (Zucker) rats.
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The activities of pathways for the biosynthesis of hippurate, urea and pyrimidines in hepatocytes isolated from lean livers were compared with those from three sources of fatty liver: a) the genetically obese Zucker rat, b) Sprague-Dawley rats fed a diet deficient in choline and inositol, and c)
Synthesis and biological evaluation of novel urea- and guanidine-based derivatives for the treatment of obesity-related hepatic steatosis.
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Leptin, the product of the obese gene, is an adipocyte-secreted protein hormone playing a key role in the progression of obesity and hepatic steatosis. In this study, 28 novel (thio)urea and guanidine-based analogues have been synthesized and
Measurement of total energy expenditure in grossly obese women: comparison of the bicarbonate-urea method with whole-body calorimetry and free-living doubly labelled water.
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OBJECTIVE
To establish validity of the bicarbonate-urea (BU) method against direct measurements of gaseous exchange (GE) in a whole-body indirect calorimeter and to compare BU and doubly labelled water (DLW) measurements in free-living conditions in the same group of grossly obese
Synthesis and evaluation of urea-based indazoles as melanin-concentrating hormone receptor 1 antagonists for the treatment of obesity.
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A series of urea-based N-1-(2-aminoethyl)-indazoles was synthesized and evaluated for melanin-concentrating hormone receptor 1 (MCHr1) antagonism in both binding and functional assays. Several compounds that acted as MCHr1 antagonists were identified, and optimization afforded a compound with
Nutrition indices in obese continuous peritoneal dialysis patients with inadequate and adequate urea clearance.
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OBJECTIVE
To test whether better nutrition is associated more with adequate urea clearance than with inadequate urea clearance in obese patients on continuous peritoneal dialysis (CPD).
METHODS
Retrospective analysis of clearance and nutrition indices in obese CPD patients. Only obese patients were
Gender, degree of obesity, and discrepancy between urea and creatinine clearance in peritoneal dialysis.
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The effect of gender and degree of obesity on the size indicators V, used to normalize urea clearance (Kt/Vur), and body surface area (BSA), used to normalize creatinine clearance (Ccr), in peritoneal dialysis was studied by: (1) mathematical comparison of the formulae used to estimate V (Watson and
Decreased urea synthesis in cafeteria-diet-induced obesity in the rat.
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Feeding rats with a cafeteria diet resulted in increases in total body weight and in epididymal-adipose-tissue weight. Those rats excreted significantly less N than did controls. The amount of N ingested by cafeteria-diet-fed rats was kept equal to that of controls. This decrease in N excretion is
Use of [14C]-sodium bicarbonate/urea to measure total energy expenditure in overweight men and women before and after low calorie diet induced weight loss.
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The aim of this study was to evaluate the use of the [14C]-sodium bicarbonate/urea technique to measure the change in total energy expenditure after weight loss and a period of weight maintenance. Eleven healthy subjects (6 men and 5 women aged 50 +/- 3 yrs, BMI 34.1 +/-2.1 kg/ m2, body fat 38.7
Novel series of substituted biphenylmethyl urea derivatives as MCH-R1 antagonists for the treatment of obesity.
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We have designed and synthesized two novel series of MCH-R1 antagonists based on a substituted biphenylmethyl urea core. SAR was explored, suggesting that optimal binding with the receptor was achieved when the biphenylmethyl group and the linker were substituted on the same nitrogen of the urea
Discovery of aryl ureas and aryl amides as potent and selective histamine H3 receptor antagonists for the treatment of obesity (part I).
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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
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