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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antagonizing the robust stimulation of food intake by neuropeptide Y represents a new potential therapeutic approach for the treatment of obesity. Earlier pharmacological studies have pointed to the Y1 and Y5 receptors as the most likely mediators of the NPY orexigenic response. In this paper, we describe a new series of small molecule Y5 antagonists derived from a 2,4-diaryl-1H-imidazole lead. The main objectives of our structural optimization efforts were to produce novel and potent Y5 antagonists with an improved oral pharmacokinetic profile and less affinity for the hERG potassium channel compared to the lead 2,4-diarylimidazole structures. These goals were accomplished by replacement of the 2-aryl ring with a cyclohexyl ring and subsequent elaboration of the 4-position of the cyclohexyl ring with a variety of hydrophilic functionalities. The resulting compound, N-(2-hydroxy-tert-butyl)(4-[4-[3-(trifluoromethyl)phenyl]imidazol-2-yl]cyclohexyl)carboxamide (20), displayed good potency at the Y5 receptor (K(i) = 3 nM), while interactions at the hERG channel were essentially eliminated (6% inhibition at a concentration of 3 microM). Importantly, the pharmacokinetic properties of 20 (F = 36%) represented a marked improvement over that of the initial 2,4-diarylimidazole structures.
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PMID:Design, synthesis, and biological evaluation of substituted 2-cyclohexyl-4-phenyl-1H-imidazoles: potent and selective neuropeptide Y Y5-receptor antagonists. 1508 30

Neuropeptide Y (NPY) is a 36 amino acid amidated peptide with high sequence homology to the endocrine peptides, peptide YY (PYY) and pancreatic polypeptide (PP). They appear to interact with a family of receptors that possess high affinity for one or more of these peptides. Five members of the receptor family have been cloned, with several additional members postulated through pharmacological evidence. All are members of the seven transmembrane domain-G-protein coupled receptor family. The Y1 receptor is the best characterised, with several nonpeptide antagonists available. This receptor appears to mediate a constriction of the peripheral vasculature and the 'anxiolytic' effects of centrally administered NPY. Less is known about the other receptors in the family. The Y2 receptor is believed to be presynaptic and mediates a reduction in neurotransmitter release. The Y4 receptor appears to be the receptor for pancreatic polypeptide, with high amounts of mRNA for this receptor found in the periphery, but lower levels in the brain. The Y5 receptor is expressed in the hypothalamus and has been postulated to be the receptor which mediates the increased food consumption seen following centrally administered NPY. Finally, the Y6 receptor has been cloned in the mouse and other species, but does not appear to encode a functional gene product in humans. Several types of nonpeptide Y1 and a series of Y5 antagonists have been described in the patent literature, though these compounds have limitations that will confine their use to preclinical studies. Nevertheless, considerable progress has been made in understanding the role of NPY and its receptors in experimental obesity. The next step will be the discovery of potent and selective nonpeptide antagonists, to add further credence to the therapeutic potential.
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PMID:Neuropeptide Y receptor antagonists in obesity. 1598 83

Neuropeptide Y (NPY) is thought to have a major role in the physiological control of energy homeostasis. Among five NPY receptors described, the NPY Y5 receptor (Y5R) is a prime candidate to mediate some of the effects of NPY on energy homeostasis, although its role in physiologically relevant rodent obesity models remains poorly defined. We examined the effect of a potent and highly selective Y5R antagonist in rodent obesity and dietary models. The Y5R antagonist selectively ameliorated diet-induced obesity (DIO) in rodents by suppressing body weight gain and adiposity while improving the DIO-associated hyperinsulinemia. The compound did not affect the body weight of lean mice fed a regular diet or genetically obese leptin receptor-deficient mice or rats, despite similarly high brain Y5R receptor occupancy. The Y5R antagonist acts in a mechanism-based manner, as the compound did not affect DIO of Y5R-deficient mice. These results indicate that Y5R is involved in the regulation and development of DIO and suggest utility for Y5R antagonists in the treatment of obesity.
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PMID:A neuropeptide Y Y5 antagonist selectively ameliorates body weight gain and associated parameters in diet-induced obese mice. 1663 93

Over the past decade, hypothalamic circuits have been described that impact energy homeostasis in rodents and humans. Our drug development efforts for the treatment of obesity and the metabolic syndrome have largely focused on selected genetic and/or pharmacologically validated pathways. The translation of these pathways into therapeutics for the treatment of obesity will find its first clinical successes over the coming decade. Initial efforts have focused on gaining a better understanding of the relevance of rodent pharmacological and genetic observations for the development of therapeutics for the treatment of human obesity. We pursue pathways defined by the expression of the ghrelin receptor, melanin-concentrating hormone receptors, melanocortin receptors, cannabinoid receptors and neuropeptide Y1 and Y5 receptors. In this review, we will discuss drug development efforts for the treatment of obesity, focused on selective melanocortin 4 receptor agonists and neuropeptide Y1 and Y5 receptor antagonists. These drug development efforts required an in-depth understanding of cell-based observations which drive the development of compound structure-activity relationships. These include understanding of receptor function in selected cell-based backgrounds and early evaluation and validation of ex vivo observations in appropriate in vivo models. In order to develop selective and safe anti-obesity drugs, diverse approaches are needed to increase the likelihood of clinical success, including: (i) developing a detailed understanding of the predictive value of rodent pathways for treatment of human disease; (ii) knowledge of the exact location of targeted receptor subtypes for the clinical indication under study in order to derive a suitable compound profile; (iii) predictive measures of in vivo and/or ex vivo receptor occupancy required to bring about a desired physiological effect; (iv) predictive parameters that outline that the drug-derived effects are safe and mechanism-based; and (v) the refinement of selected compound classes, aimed at their clinical use.
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PMID:Design and synthesis of (ant)-agonists that alter appetite and adiposity. 1687 70

Neuropeptide Y (NPY) is a potent orexigenic neuropeptide, and antagonism of NPY Y1 and NPY Y5 receptors (NPYxR) is considered a potentially important anti-obesity drug target. We tested the hypothesis that blockade of the NPY5R will lead to weight loss in humans using MK-0557, a potent, highly selective, orally active NPY5R antagonist. The initial series of experiments reported herein, including a multiple-dose positron-emission tomography study and a 12 week proof-of concept/dose-ranging study, suggested an optimal MK-0557 dose of 1 mg/day. The hypothesis was then tested in a 52 week, multicenter, randomized, double-blind, placebo-controlled trial involving 1661 overweight and obese patients. Although statistically significant at 52 weeks, the magnitude of induced weight loss was not clinically meaningful. These observations provide the first clinical insight into the human NPY-energy homeostatic pathway and suggest that solely targeting the NPY5R in future drug development programs is unlikely to produce therapeutic efficacy.
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PMID:Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adults. 1701 98

A conventional QSAR study has been carried out using thermodynamic and other descriptors, on a set of arylsulfonamidomethylcyclohexyl derivatives as antagonists of potential obesity drug target human neuropeptide Y Y5 receptor. In addition, a novel range based method was applied to obtain a QSAR model so that the information contained in the compounds for which an approximate value instead of exact value of inhibitory activity was available could be included in the model. Analysis of models suggests that range based model is better in screening biologically active compounds from chemical library. The conventional model is able to predict activity accurately only for active compounds whereas the range based method is better in discriminating active and inactive compounds.
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PMID:A novel range based QSAR study of human neuropeptide Y (NPY) Y5 receptor inhibitors. 1708 99

The neuropeptide Y (NPY) family of peptides and receptors regulate food intake. Inherited variation in this pathway could influence susceptibility to obesity and its complications, including type 2 diabetes. We genotyped a set of 71 single nucleotide polymorphisms (SNPs) that capture the most common variation in NPY, PPY, PYY, NPY1R, NPY2R, and NPY5R in 2,800 individuals of recent European ancestry drawn from the near extremes of BMI distribution. Five SNPs located upstream of NPY2R were nominally associated with BMI in men (P values = 0.001-0.009, odds ratios [ORs] 1.27-1.34). No association with BMI was observed in women, and no consistent associations were observed for other genes in this pathway. We attempted to replicate the association with BMI in 2,500 men and tested these SNPs for association with type 2 diabetes in 8,000 samples. We observed association with BMI in men in only one replication sample and saw no association in the combined replication samples (P = 0.154, OR = 1.09). Finally, a 9% haplotype was associated with type 2 diabetes in men (P = 1.73 x 10(-4), OR = 1.36) and not in women. Variation in this pathway likely does not have a major influence on BMI, although small effects cannot be ruled out; NPY2R should be considered a candidate gene for type 2 diabetes in men.
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PMID:Association studies of BMI and type 2 diabetes in the neuropeptide Y pathway: a possible role for NPY2R as a candidate gene for type 2 diabetes in men. 1732 59

We examined the genetic association of neuropeptide Y receptor Y5 (NPY5R) single nucleotide polymorphisms (SNPs) with measures of the insulin resistance (metabolic) syndrome. We genotyped 10 NPY5R SNPs in 439 Mexican American individuals (age=43.3+/-17.3 years and BMI=30.0+/-6.7 kg/m2) distributed across 27 pedigrees from the San Antonio Family Diabetes Study and performed association analyses using the measured genotype approach as implemented in Sequential Oligogenic Linkage Analysis Routines (SOLAR). Minor alleles for five (rs11100493, rs12501691, P1, rs11100494, rs12512687) of the NPY5R SNPs were found to be significantly (p<0.05) associated with fasting plasma triglyceride concentrations and decreased high-density lipoprotein concentrations. In addition, the minor allele for SNP P2 was significantly associated (p=0.031) with a decreased homeostasis model assessment of beta-cell function (HOMA-%beta). Linkage disequilibrium between SNP pairs indicated one haplotype block of five SNPs (rs11100493, rs12501691, P1, rs11100494, rs12512687) that were highly correlated (r2>0.98). These preliminary results provide evidence for association of SNPs in the NPY5R gene with dyslipidemia (elevated triglyceride concentrations and reduced high-density lipoprotein levels) in our Mexican American population.
Obesity (Silver Spring) 2007 Apr
PMID:Association of neuropeptide Y receptor Y5 polymorphisms with dyslipidemia in Mexican Americans. 1742 13

We have derived a novel series of neuropeptide Y (NPY) Y5 receptor antagonists from the biphenylurea 3. Cyclohexylurea 21c, a member of the series, is a potent NPY Y5 receptor antagonist that exhibits excellent pharmacokinetic parameters in rats and dogs. On chronic oral administration to diet-induced obese rats, 21c displayed an anti-obesity profile, causing a modest reduction in food intake, a significant decrease in body weight gain, a decrease in adipose mass, and an increase in lean tissue mass.
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PMID:Discovery of novel orally active ureido NPY Y5 receptor antagonists. 1816 Feb 82

The increased synthesis and release of neuropeptide Y (NPY) in the hypothalamus participate in the development of overeating and obesity in the Zucker fa/fa rat. The orexigenic effects of NPY are mediated through the Y1 and Y5 receptors. The substitution of [D-Trp34] in the NPY amino-acid sequence increases selectivity without lowering potency at the Y5 receptor. In the present study, to address the role of the NPY Y5 receptor in obesity, we investigated the acute effect of [D-Trp 34]-NPY in lean and obese Zucker rats. Obese rats were markedly hyperphagic (27.1 +/- 0.6 vs. 18.7 +/- 0.4 (lean) g/day; p < 0.01). Injection of [D-Trp34]-NPY in the lateral brain ventricle at a dose of 16 microg stimulated food intake to the same extent in both lean (p < 0.01) and obese (p < 0.01) rats 1 h after injection. This effect was still observed after 6 h (p < 0.01). These results indicate, therefore, that the obese rats are responsive to [D-Trp34]-NPY. They support the role of the neuropeptide Y5 receptor in the regulation of food intake and suggest that NPY Y5 antagonism might be useful for treating obesity.
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PMID:Responsiveness of obese Zucker rats to [D-Trp34]-NPY supports the targeting of Y5 receptor for obesity treatment. 1828 29


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