共查询到20条相似文献,搜索用时 31 毫秒
1.
Toshiyuki Takahashi Yuji Haga Toshihiro Sakamoto Minoru Moriya Osamu Okamoto Katsumasa Nonoshita Takunobu Shibata Takuya Suga Hirobumi Takahashi Tomoko Hirohashi Aya Sakuraba Akira Gomori Hisashi Iwaasa Tomoyuki Ohe Akane Ishihara Yasuyuki Ishii Akio Kanatani Takehiro Fukami 《Bioorganic & medicinal chemistry letters》2009,19(13):3511-3516
Continuing medicinal chemistry studies to identify spiropiperidine-derived NPY Y5 receptor antagonists are described. Aryl urea derivatives of a variety of spiropiperidines were tested for their NPY Y5 receptor binding affinities. Of the spiropiperidines so far examined, spiro[3-oxoisobenzofurane-1(3H),4′-piperidine] was a useful scaffold for producing orally active NPY Y5 receptor antagonists. Oral administration of 5c significantly inhibited the Y5 agonist-induced food intake in rats with a minimum effective dose of 3 mg/kg. In addition, this compound was efficacious in decreasing body weight in diet-induced obese mice. 相似文献
2.
Minoru Kameda Kensuke Kobayashi Hirokatsu Ito Hiroshi Miyazoe Toshiaki Tsujino Chisato Nakama Hiroshi Kawamoto Makoto Ando Sayaka Ito Tomoki Suzuki Tetsuya Kanno Takeshi Tanaka Yoshio Tahara Takeshi Tani Sachiko Tanaka Shigeru Tokita Nagaaki Sato 《Bioorganic & medicinal chemistry letters》2009,19(15):4325-4329
The synthesis and evaluation of a series of 2,4-diaminopyridine-based neuropeptide Y Y1 (NPY Y1) receptor antagonists are described. Compound 1 was previously reported by our laboratory to be a potent and selective Y1 antagonist; however, 1 was also found to have potent hERG inhibitory activity. The main focus of this communication is structure–activity relationship development aimed at eliminating the hERG activity of 1. This resulted in the identification of compound 3d as a potent and selective NPY Y1 antagonist with reduced hERG liability. 相似文献
3.
Yuji Haga Toshihiro Sakamoto Takunobu Shibata Katsumasa Nonoshita Makoto Ishikawa Takuya Suga Hirobumi Takahashi Toshiyuki Takahashi Hidekazu Takahashi Makoto Ando Takashi Murai Akira Gomori Zenjun Oda Hidefumi Kitazawa Yuko Mitobe Maki Kanesaka Tomoyuki Ohe Hisashi Iwaasa Yasuyuki Ishii Akane Ishihara Takehiro Fukami 《Bioorganic & medicinal chemistry》2009,17(19):6971-6982
A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide derivatives were synthesized to identify potent NPY Y5 receptor antagonists. Of the compounds, 21j showed high Y5 binding affinity, metabolic stability and brain and cerebrospinal fluid (CSF) penetration, and low susceptibility to P-glycoprotein transporters. Oral administration of 21j significantly inhibited the Y5 agonist-induced food intake in rats with a minimum effective dose of 1 mg/kg. This compound was selected for proof-of-concept studies in human clinical trials. 相似文献
4.
Hirobumi Takahashi Yuji Haga Takunobu Shibata Katsumasa Nonoshita Toshihiro Sakamoto Minoru Moriya Tomoyuki Ohe Masato Chiba Yuko Mitobe Hidefumi Kitazawa Hisashi Iwaasa Akane Ishihara Yasuyuki Ishii Akio Kanatani Takehiro Fukami 《Bioorganic & medicinal chemistry letters》2009,19(18):5436-5439
A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide derivatives were synthesized and profiled for NPY Y5 binding affinity, brain and CSF penetrability in rats, and susceptibility to human and mouse P-glycoprotein transporters in order to develop a PET ligand. Compound 12b exhibited an acceptable profile for a PET ligand, and [11C]12b was successfully utilized in clinical settings as a Y5 PET ligand. 相似文献
5.
Toshihiro Sakamoto Minoru Moriya Hiroyasu Tsuge Toshiyuki Takahashi Yuji Haga Katsumasa Nonoshita Osamu Okamoto Hirobumi Takahashi Aya Sakuraba Tomoko Hirohashi Takunobu Shibata Tetsuya Kanno Junko Ito Hisashi Iwaasa Akira Gomori Akane Ishihara Takahiro Fukuroda Akio Kanatani Takehiro Fukami 《Bioorganic & medicinal chemistry》2009,17(14):5015-5026
Spiroindoline urea derivatives, designed to act as NPY Y5 receptor antagonists, were synthesized and their structure–activity relationships were investigated. Of these derivatives, compound 3a showed good Y5 binding affinity with favorable pharmacokinetic properties. Compound 3a significantly inhibited bPP Y5 agonist-induced food intake in rats, and suppressed body weight gain in DIO mice. 相似文献
6.
Nesrin Gökhan-Kelekçi Semra Koyunoğlu Samiye Yabanoğlu Kemal Yelekçi Özen Özgen Gülberk Uçar Kevser Erol Engin Kendi Akgül Yeşilada 《Bioorganic & medicinal chemistry》2009,17(2):675-689
A new series of pyrazoline derivatives were prepared starting from a quinazolinone ring and evaluated for antidepressant, anxiogenic and MAO-A and -B inhibitory activities by in vivo and in vitro tests, respectively. Most of the synthesized compounds showed high activity against both the MAO-A (compounds 4a–4h, 4j–4n, and 5g–5l) and the MAO-B (compounds 4i and 5a–5f) isoforms. However, none of the novel compounds showed antidepressant activity except for 4b. The reason for such biological properties was investigated by computational methods using recently published crystallographic models of MAO-A and MAO-B. The differences in the intermolecular hydrophobic and H-bonding of ligands to the active site of each MAO isoform were correlated to their biological data. Compounds 4i, 4k, 5e, 5i, and 5l were chosen for their ability to reversibly inhibit MAO-B and MAO-A and the availability of experimental inhibition data. Observation of the docked positions of these ligands revealed interactions with many residues previously reported to have an effect on the inhibition of the enzyme. Among the pyrazoline derivatives, it appears that the binding interactions for this class of compounds are mostly hydrophobic. All have potential edge-to-face hydrophobic interactions with F343, as well as π–π stacking with Y398 and other hydrophobic interactions with L171. Strong hydrophobic and H-bonding interactions in the MAO recognition of 4i could be the reason why this compound shows selectivity toward the MAO-B isoform. The very high MAO-B selectivity for 4i can be also explained in terms of the distance between the FAD and the compound, which was greater in the complex of MAO-A-4i as compared to the corresponding MAO-B complex. 相似文献
7.
Guanglin Luo Ling Chen Shuanghua Hu Yazhong Huang Gail Mattson Lawrence G. Iben John W. Russell Wendy J. Clarke John B. Hogan Ildiko Antal-Zimanyi Graham S. Poindexter 《Bioorganic & medicinal chemistry letters》2013,23(13):3814-3817
A convergent synthesis route for the heterocyclic modification of a novel bicyclo[3.1.0]hexane NPY1 antagonist 2 was developed and the structure activity relationship of these modifications on NPY1 binding is reported. Two heterocyclic analogs 9 and 10 showed comparable Y1 binding potency to 2, but with improved aqueous solubility. Compound 9 demonstrated reduced spontaneous nocturnal food intake in a rat model when dosed ip. Compound 9 was also shown to be orally bioavailable and brain penetrable. 相似文献
8.
Discovery and structure–activity relationship of a novel spirocarbamate series of NPY Y5 antagonists
Colin P. Leslie Jonathan Bentley Matteo Biagetti Stefania Contini Romano Di Fabio Daniele Donati Thorsten Genski Sebastien Guery Angelica Mazzali Giancarlo Merlo Domenica A. Pizzi Fabiola Sacco Catia Seri Michela Tessari Laura Zonzini Laura Caberlotto 《Bioorganic & medicinal chemistry letters》2010,20(20):6103-6107
A novel series of trans-8-aminomethyl-1-oxa-3-azaspiro[4.5]decan-2-one derivatives was identified with potent NPY Y5 antagonist activity. Optimization of the original lead furnished compounds 23p and 23u, which combine sub-nanomolar Y5 activity with metabolic stability, oral bioavailability, brain penetration and strong preclinical profile for development. Both compounds significantly inhibited the food intake induced by a Y5 selective agonist with minimal effective doses of 3 mg/kg po. 相似文献
9.
《Peptides》2013
Accumulating data implicate a pathological role for sympathetic neurotransmitters like neuropeptide Y (NPY) in breast cancer progression. Our group and others reported that NPY promotes proliferation and migration in breast cancer cells, however the angiogenic potential of NPY in breast cancer is unknown. Herein we sought to determine if NPY promotes angiogenesis in vitro by increasing vascular endothelial growth factor (VEGF) expression and release from 4T1 breast cancer cells. Western blot analysis revealed that NPY treatment caused a 52 ± 14% increase in VEGF expression in the 4T1 cells compared to non-treated controls. Using selective NPY Y-receptor agonists (Y1R, Y2R and Y5R) we observed an increase in VEGF expression only when cells were treated with Y5R agonist. Congruently, using selective Y1R, Y2R, or Y5R antagonists, NPY-induced increases in VEGF expression in 4T1 cells were attenuated only under Y5R antagonism. Endothelial tube formation assays were conducted using conditioned media (CM) from NPY treated 4T1 cells. Concentration-dependent increases in number of branch points and complete endothelial networks were observed in HUVEC exposed to NPY CM. CM from Y5R agonist treated 4T1 cells caused similar increases in number of branch points and complete endothelial networks. VEGF concentration was quantified in CM (ELISA) from agonist experiments; we observed a 2-fold and 2.5-fold increase in VEGF release from NPY and Y5R agonist treated 4T1 cells respectively. Overall these data highlight a novel mechanism by which NPY may promote breast cancer progression, and further implicate a pathological role of the NPY Y5R. 相似文献
10.
Minoru Kameda Makoto Ando Chisato Nakama Kensuke Kobayashi Hiroshi Kawamoto Sayaka Ito Tomoki Suzuki Takeshi Tani Satoshi Ozaki Shigeru Tokita Nagaaki Sato 《Bioorganic & medicinal chemistry letters》2009,19(17):5124-5127
A series of 2,4-diaminopyridine derivatives was synthesized and evaluated as potential candidates for neuropeptide Y (NPY) Y1 receptor positron emission tomography (PET) tracers. Derivatives bearing substitutions allowing reliable access to radiolabeling were designed, focusing on Y1 binding affinity and lipophilicity. The advanced derivatives 2n and 2o were identified as promising PET tracer candidates. 相似文献
11.
Lloyd T.J. Evans F. Geoffrey N. Cloke Peter B. Hitchcock 《Inorganica chimica acta》2010,363(6):1114-147
A series of mono- and bis-amide scandium and yttrium compounds incorporating the furyl-substituted disilazide ligand, [N{SiMe2R}2]− {i} (where R = 2-methylfuryl) have been synthesized. The compounds Sc{i}Cl2 (1), Sc{i}(CH2SiMe3)2 (2) and Sc{i}(OAr)2 (3) were made from suitable scandium starting materials employing either a salt metathesis protocol with Li{i} or via protonolysis of Sc-C bonds by the neutral amine H{i}. The thermally unstable bis-alkyl yttrium compound, ‘Y{i}(CH2SiMe3)2’ was isolated as the bis-THF adduct (4) and the bis-aryloxide Y{i}(OAr)2 (5) was synthesized by elimination of LiOAr from Y(OAr)3. The bis-amide complex Y{i}2Cl (6) and conversion to a rare example of an yttrium benzyl compound Y{i}2(CH2Ph) (7) are described. The yttrium cation, [Y{i}2]+, was synthesized by benzyl abstraction from 7 using B(C6F5)3. Structural characterization of representative examples show variation in the coordination modes for amide ligand {i}, differing primarily in the number of furyl groups that coordinate to the metal, with examples in which zero, one or two M-Ofuryl bonds are present. Preliminary investigation in two areas of catalysis are presented. 相似文献
12.
New series of triazole-containing 3-phenylcoumarin–lipoic acid conjugates were designed as multi-functional agents for treatment of Alzheimer's disease. The target compounds 4a-o were synthesized via the azide-alkyne cycloaddition reaction and their biological activities were primarily evaluated in terms of neuroprotection against H2O2-induced cell death in PC12 cells and AChE/BuChE inhibition. The promising compounds 4j and 4i containing four carbons spacer were selected for further biological evaluations. Based on the obtained results, the benzocoumarin derivative 4j with IC50 value of 7.3 µM was the most potent AChE inhibitor and displayed good inhibition toward intracellular reactive oxygen species (ROS). This compound with antioxidant and metal chelating ability showed also protective effect on cell injury induced by Aβ1-42 in SH-SY5Y cells. Although the 8-methoxycoumarin analog 4i was slightly less active than 4j against AChE, but displayed higher protection ability against H2O2-induced cell death in PC12 and could significantly block Aβ-aggregation. The results suggested that the prototype compounds 4i and 4j might be promising multi-functional agents for the further development of the disease-modifying treatments of Alzheimer's disease. 相似文献
13.
Seetharama D. S. Jois Latha M. Nagarajarao M. Prabhakaran A. Balasubramaniam 《Journal of biomolecular structure & dynamics》2013,31(1):497-508
Abstract Neuropeptide Y (NPY), receptors belong to the G-protein coupled receptor superfamily. NPY mediates several physiological responses, such as blood pressure, food intake, sedation. These actions of NPY are mediated by six receptor subtypes denoted as Y1-Y5 and y6. Modeling of receptor subtypes and binding site identification is an important step in developing new therapeutic agents. We have attempted to model the three NPY receptor types, Y1, Y4, and Y5 using homology modeling and threading methods. The models are consistent with previously reported experimental evidence. To understand the interaction and selectivity of NPY analogues with different neuropeptide receptors, docking studies of two neuropeptide analogues (BVD10 and BVD15) with receptors Y1 and Y4 were carried out. Results of the docking studies indicated that the interaction of ligands BVD10 and BVD15 with Y1 and Y4 receptors are different. These results were evaluated for selectivity of peptide analogues BVD10 and BVD15 towards the receptors. 相似文献
14.
Kaimei Cho Makoto Ando Kensuke Kobayashi Hiroshi Miyazoe Toshiaki Tsujino Sayaka Ito Tomoki Suzuki Takeshi Tanaka Shigeru Tokita Nagaaki Sato 《Bioorganic & medicinal chemistry letters》2009,19(16):4781-4785
A novel series of cyclohexanamine derivatives was designed and synthesized as potent and selective human neuropeptide Y Y1 receptor antagonists. Modification of high-throughput screening hit compound 1 resulted in the identification of compound 3i, which displays potent Y1 activity and good selectivity towards hERG K+ channel and serotonin transporter. 相似文献
15.
Max Keller Melanie Kaske Tobias Holzammer Günther Bernhardt Armin Buschauer 《Bioorganic & medicinal chemistry》2013,21(21):6303-6322
The structurally related peptides neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) are endogenous agonists of the NPY receptor (YR) family, which in humans comprises four functionally expressed subtypes, designated Y1R, Y2R, Y4R and Y5R. Nonpeptide antagonists with high affinity and selectivity have been described for the Y1R, Y2R and Y5R, but such compounds are still lacking for the Y4R. In this work, the structures of the high affinity selective (R)-argininamide-type Y1R antagonists BIBP3226 and BIBO3304 were linked via the guanidine or urea moieties to give homo-dimeric argininamides with linker lengths ranging from 31 to 41 atoms. Interestingly, the twin compounds proved to be by far less selective for the Y1R than the R-configured monovalent parent compounds. The decrease in selectivity ratio was most pronounced for Y1R versus Y4R subtype, resulting in comparable affinities of bivalent ligands for Y1R and Y4R (e.g. UR-MK177 ((R,R)-49): Ki = 230 nM (Y1R) and 290 nM (Y4R)). With a Ki value of 130 nM and a Kb value of 20 nM, UR-MK188 ((R,R)-51) was superior to all Y4R antagonists known to date. The S,S-configured optical antipodes of UR-MK177 and UR-MK188 (UR-MEK381 ((S,S)-49) and UR-MEK388 ((S,S)-51)) were synthesized to investigate the stereochemical discrimination by the different receptor subtypes. Whereas preference for R,R-configured argininamides was characteristic of the Y1R, stereochemical discrimination by the Y4R was not observed. This may pave the way to selective Y4R antagonists. 相似文献
16.
RALF ZIEMEK ERICH SCHNEIDER ANJA KRAUS CHIARA CABRELE ANNETTE G. BECK-SICKINGER GÜNTHER BERNHARDT 《Journal of receptor and signal transduction research》2013,33(4):217-233
Fluorescence-labeled neuropeptide Y (NPY) has been used in flow cytometric binding assays for the determination of affinity constants of NPY Y1, Y2, and Y5 receptor ligands. Because the binding of fluorescent NPY is insufficient for competition studies at the human Y4 receptor (hY4R), we replaced Glu-4 in hPP with Lys for the derivatization with cyanine-5. Because cy5-[K4]hPP has high affinity (Kd 5.6 nM) to the hY4R, it was used as a probe in a flow cytometric binding assay. Specific binding of cy5-[K4]hPP to hY4R was visualized by confocal microscopy. The hY4R, the chimeric G protein Gqi5 and mitochondrially targeted apoaequorin were stably coexpressed in CHO cells. Aequorin luminescence was quantified in a microplate reader and by a CCD camera. By application of these methods 3-cyclohexyl-N-[(3-1H-imidazol-4-ylpropylamino)(imino)methyl]propanamide (UR-AK49) was discovered as the first nonpeptidic Y4R antagonist (pKi 4.17), a lead to be optimized in terms of potency and selectivity. 相似文献
17.
Miki Watanabe Sulaiman Sheriff Nijiati Kadeer Junho Cho Kenneth B. Lewis Ambikaipakan Balasubramaniam Michael A. Kennedy 《Metabolomics : Official journal of the Metabolomic Society》2012,8(5):854-868
Overexpression of neuropeptide Y (NPY) and its receptors has been found in various cancers. In our previous study, we demonstrated expression of NPY Y5 receptor (Y5R) in various breast cancer cell lines along with Y1 receptor. In Y5R expressing BT-549 cells, NPY induced cell proliferation that was blocked by Y5R-selective antagonist CGP1683A (CGP). Here, NMR-based metabonomics was used to monitor the metabolic profile of BT-549 cells in the presence of NPY and CGP to assess the effect of Y5R activation and inhibition during NPY-induced cell proliferation. To study changes in intra and extra cellular metabolites in response to various treatments, 1D 1H-NMR spectra of both hydrophilic cell extracts and growth medium were recorded from BT-549 with three treatments: (1) NPY, (2) CGP, and (3) CGP followed by NPY (CGP/NPY). Principal component analysis and statistical significance analysis indicated changes in intracellular concentrations of seven metabolites in hydrophilic cell extracts with NPY treatment: decreases in lactate, succinate, myo-inositol, and creatine, and increases in acetate, glutamate, and aspartate. A significant increase in intracellular lactate level and attenuation of other metabolites to baseline was detected in CGP/NPY group. Also, significant decreases in lactate and increases in pyruvate were observed in growth medium from NPY treated cells. Based on the metabonomics analysis, Y5R activation induces cell proliferation by increasing the rate of glycolysis, glutaminolysis, and TCA cycle. Inhibition of Y5R by CGP counteracts NPY-induced changes in cellular metabolites. These changes may play a role in cell proliferation and migration by NPY through Y5R activation. 相似文献
18.
Brigitte Guérin Véronique Dumulon-Perreault Marie-Claude Tremblay Samia Ait-Mohand Patrick Fournier Céléna Dubuc Simon Authier François Bénard 《Bioorganic & medicinal chemistry letters》2010,20(3):950-953
We substituted a truncated neuropeptide Y (NPY) analog, [Pro30, Tyr32, Leu34]NPY(28-36)NH2 also called BVD15, at various positions with DOTA (1,4,7,10-tetraazacyclododecane-1,4,7-10-tetraacetic acid) and evaluated the effect of the coupling position with the binding affinity for NPY Y1 receptors (NPY1R). Our data suggest that [Lys(DOTA)4]BVD15 (Ki = 63 ± 25 nM vs. Ki = 39 ± 34 nM for BVD15) is a potent NPY analog suitable for radiolabeling with metallo positron emitters for PET imaging of breast cancer. 相似文献
19.
Objective: Neuropeptide Y (NPY), a 36‐amino acid peptide with orexigenic properties, is expressed abundantly in the central nervous system and binds to several NPY receptor subtypes. This study examines the roles of the NPY Y1, Y2, and Y5 receptor(s) in energy homeostasis. Research Methods and Procedures: We administered intracerebroventricular NPY (3 μg/d) or selective peptide agonists for the Y1, Y2, and Y5 receptor subtypes to C57Bl/6 mice for 6 days by mini‐osmotic pumps to assess the role of each receptor subtype in NPY‐induced obesity. Energy expenditure (EE) and respiratory quotient (RQ) were studied using indirect calorimetry. Adiposity was measured by DXA scanning and fat pad dissection. Insulin sensitivity was tested by whole‐blood glucose measurement after an insulin challenge. Results: Central administration of the selective Y1 agonist, Y5 agonist, or NPY for 6 days in mice significantly increased body weight, adiposity, and RQ, with significant hyperphagia in the Y5 agonist‐ and NPY‐treated groups but not in the Y1 agonist‐treated group. The NPY, Y1, or Y5 agonist‐treated mice had little change in total EE during ad libitum and pair‐feeding conditions. Conversely, selective activation of the Y2 receptor reduced feeding and resulted in a significant, but transient, weight loss. Discussion: Central activation of both Y1 and Y5 receptors increases RQ and adiposity, whereas only Y5 receptor activation reduces energy expended per energy ingested. Selective activation of Y2 autoreceptors leads to hypophagia and transient weight loss, with little effect on total EE. Our study indicates that all three NPY receptor subtypes may play a role in regulating energy homeostasis in mice. 相似文献
20.
Gillian E. Lunniss Ashley A. Barnes Nick Barton Matteo Biagetti Federica Bianchi Stephen M. Blowers Laura Caberlotto Amanda Emmons Ian P. Holmes Dino Montanari Ros Norris Dewi J. Walters Steve P. Watson 《Bioorganic & medicinal chemistry letters》2009,19(15):4022-4025
A novel small molecule NPY Y2 antagonist (3) identified from high throughput screening is described. A subsequent SAR study and optimisation programme based around this molecule is also described, leading to the identification of potent and soluble pyridyl analogue 36. 相似文献