共查询到20条相似文献,搜索用时 15 毫秒
1.
Zarrinmayeh H Zimmerman DM Cantrell BE Schober DA Bruns RF Gackenheimer SL Ornstein PL Hipskind PA Britton TC Gehlert DR 《Bioorganic & medicinal chemistry letters》1999,9(5):647-652
A series of benzimidazoles (4) was synthesized and evaluated in vitro as potent and selective NPY Y1 receptor antagonists. Substitution of the piperidine nitrogen of 4 with appropriate R groups resulted in compounds with more than 80-fold higher affinity at the Y receptor compared to the parent compound 5 (R = H). The most potent benzimidazole in this series was 21 (Ki = 0.052 nM). 相似文献
2.
Y Murakami S Hagishita T Okada M Kii H Hashizume T Yagami M Fujimoto 《Bioorganic & medicinal chemistry》1999,7(8):1703-1714
A novel class of potent and selective non-peptide neuropeptide Y (NPY) Y1 receptor antagonists, having benzazepine nuclei, have been designed, synthesized, and evaluated for activity. Through a blind screening we found the compound 1-N-(3-(N'-(tert-butoxycarbonyl)amino)benzyl)-7-methoxy-(3-(3)-methyl ureido)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (9: IC50 = 1.6 microM). Chemical modifications of 9 gave a potent NPY Y1 antagonist 3-(N-(4-hydroxyphenyl)-N'-methylguanidino)-1-N-(3-(N'-(tert-butoxy carbonyl)amino)benzyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (14c: IC5(0=43 nM), which had no affinity for NPY Y2 and Y5 receptors. 相似文献
3.
Dihydropyridine neuropeptide Y Y(1) receptor antagonists 总被引:3,自引:0,他引:3
Poindexter GS Bruce MA LeBoulluec KL Monkovic I Martin SW Parker EM Iben LG McGovern RT Ortiz AA Stanley JA Mattson GK Kozlowski M Arcuri M Antal-Zimanyi I 《Bioorganic & medicinal chemistry letters》2002,12(3):379-382
Dihydropyridine 5a was found to be an inhibitor of neuropeptide Y(1) binding in a high throughput (125)I-PYY screening assay. Structure-activity studies around certain portions of the dihydropyridine chemotype identified BMS-193885 (6e) as a potent and selective Y(1) receptor antagonist. In a forskolin-stimulated c-AMP production assay using CHO cells expressing the human Y(1) receptor, 6e demonstrated full functional antagonism (K(b)=4.5 nM). Compound 6e inhibited NPY-induced feeding in satiated rats when dosed at 3.0 and 10.0 mg/kg (ip), and also decreased spontaneous overnight food consumption in rats at doses of 10 and 20 mg/kg (ip). 相似文献
4.
Fox BM Natero R Richard K Connors R Roveto PM Beckmann H Haller K Golde J Xiao SH Kayser F 《Bioorganic & medicinal chemistry letters》2011,21(8):2460-2467
We discovered novel pyrrolidine MCHR1 antagonist 1 possessing moderate potency. Profiling of pyrrolidine 1 demonstrated that it was an inhibitor of the hERG channel. Investigation of the structure-activity relationship of this class of pyrrolidines allowed us to optimize the MCHR1 potency and decrease the hERG inhibition. Increasing the acidity of the amide proton by converting the benzamide in lead 1 to an anilide provided single digit nanomolar MCHR1 antagonists while replacing the dimethoxyphenyl ring of 1 with alkyl groups possessing increased polarity dramatically reduced the hERG inhibition. 相似文献
5.
The identification of a series of novel, soluble non-peptidic neuropeptide Y Y2 receptor antagonists
Lunniss GE Barnes AA Barton N Biagetti M Bianchi F Blowers SM Caberlotto LL Emmons A Holmes IP Montanari D Norris R Puckey GV Walters DJ Watson SP Willis J 《Bioorganic & medicinal chemistry letters》2010,20(24):7341-7344
The identification and subsequent optimisation of a selective non-peptidic NPY Y2 antagonist series is described. This led to the development of amine 2, a selective, soluble NPY Y2 receptor antagonist with enhanced CNS exposure. 相似文献
6.
Jablonowski JA Chai W Li X Rudolph DA Murray WV Youngman MA Dax SL Nepomuceno D Bonaventure P Lovenberg TW Carruthers NI 《Bioorganic & medicinal chemistry letters》2004,14(5):1239-1242
Through SAR studies of a piperidinylindoline cinnamide HTS lead, the first potent, non-peptide, low molecular weight selective Neuropeptide Y Y2 (NPY Y2) antagonists have been synthesized. The SAR studies around the piperidinyl, the indolinyl, and the cinnamyl moieties are discussed. 相似文献
7.
Dove S Michel MC Knieps S Buschauer A 《Canadian journal of physiology and pharmacology》2000,78(2):108-115
The design of non-peptide, Y1-selective antagonists of neuropeptide Y (NPY) as pharmacological tools is in progress and is increasingly important as therapeutic applications are expected. Starting from the potent histamine H2 agonist and weak NPY Y1 antagonist arpromidine, 16 imidazolylpropylguanidine derivatives were synthesized and tested for Y1 antagonistic activity (inhibition of NPY-stimulated Ca2+ increase in human erythroleukemic cells), where the pheniramine-like moiety of arpromidine was replaced with 2-pyridylaminoalkyl, benzyl-(2-pyridyl)aminoalkyl, and phenyl-(2-pyridyl)alkylaminoalkyl partial structures derived from mepyramine. The pA2 values of the most active compounds are in the range of 6.2-6.5. Quantitative structure-activity relationships (QSAR) were investigated by fragment regression analysis. Results indicate that a tetramethylene spacer between the guanidino group and the amino nitrogen is optimal. For an at least moderate degree of Y1 antagonistic activity, a second benzyl or phenyl group must be present in addition to the 2-pyridyl ring. At this second group, hydrophobic substituents such as 3,4-di-CI and 4-Br further enhance Y1 antagonism. The most active derivative additionally bears a 5-Br substituent at the 2-pyridyl moiety. Structure-activity relationships suggest that the compounds might be able to partially imitate the role of NPY when interacting with Y1 receptors and thus behave as moderate non-peptide NPY Y1 antagonists. 相似文献
8.
Poindexter GS Bruce MA Breitenbucher JG Higgins MA Sit SY Romine JL Martin SW Ward SA McGovern RT Clarke W Russell J Antal-Zimanyi I 《Bioorganic & medicinal chemistry》2004,12(2):507-521
Structure-activity studies around the urea linkage in BMS-193885 (4a) identified the cyanoguanidine moiety as an effective urea replacement in a series of dihydropyridine NPY Y(1) receptor antagonists. In comparison to urea 4a (K(i)=3.3 nM), cyanoguanidine 20 (BMS-205749) displayed similar binding potency at the Y(1) receptor (K(i)=5.1 nM) and full functional antagonism (K(b)=2.6 nM) in SK-N-MC cells. Cyanoguanidine 20 also demonstrated improved permeability properties in Caco-2 cells in comparison to urea 4a (43 vs 19 nm/s). 相似文献
9.
Aiglstorfer I Hendrich I Moser C Bernhardt G Dove S Buschauer A 《Bioorganic & medicinal chemistry letters》2000,10(14):1597-1600
Analogues of BIBP 3226, (R)-N(alpha)-diphenylacetyl-N-(4-hydroxybenzyl)argininamide, were synthesized and investigated for Y1 antagonism (Ca2+-assay, HEL cells) and binding on Y1, Y2 and Y5 receptors. Replacing the benzylamino by a tetrahydrobenzazepinyl group preserves most of the Y1 activity. Combination with a N(G)-phenylpropyl arginine and a N(alpha)-p-biphenylylacetyl moiety shifted the NPY receptor selectivity towards Y5. 相似文献
10.
Zhang X Hufnagel H Markotan T Lanter J Cai C Hou C Singer M Opas E McKenney S Crysler C Johnson D Sui Z 《Bioorganic & medicinal chemistry letters》2011,21(18):5577-5582
A series of 4-azetidinyl-1-aryl-cyclohexanes as potent CCR2 antagonists with high selectivity over activity for the hERG potassium channel is discovered through divergent SARs of CCR2 and hERG. 相似文献
11.
Rueeger H Rigollier P Yamaguchi Y Schmidlin T Schilling W Criscione L Whitebread S Chiesi M Walker MW Dhanoa D Islam I Zhang J Gluchowski C 《Bioorganic & medicinal chemistry letters》2000,10(11):1175-1179
The design of a novel series of NPY-Y5 receptor antagonists is described. Key elements for the design were the identification of weak Y5 hits from a Y1 program, results from a combinatorial approach and database mining. This led to the discovery of the quinazoline 4 and the aryl-sulphonamide moiety as major components of the pharmacophore for Y5 affinity. The synthesis and SAR towards CGP71683A is described. 相似文献
12.
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
13.
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
14.
Griffith DA Hargrove DM Maurer TS Blum CA De Lombaert S Inthavongsay JK Klade LE Mack CM Rose CR Sanders MJ Carpino PA 《Bioorganic & medicinal chemistry letters》2011,21(9):2641-2645
A novel series of pyrazolo[1,5-a]pyrimidine derivatives was synthesized and evaluated as NPY Y1R antagonists. High binding affinity and selectivity were achieved with C3 trisubstituted aryl groups and C7 substituted 2-(tetrahydro-2H-pyran-4-ylamino)ethylamine moieties. Efforts to find close analogs with low plasma clearance in the rat and minimal p-glycoprotein efflux in the mouse were unsuccessful. Compound 2f (CP-671906) inhibited NPY-induced increases in blood pressure and food intake after iv and icv administration, respectively, in Sprague-Dawley (SD) rat models. Oral administration of compound 2f resulted in a modest, but statistically significant, reduction in food intake in a Wistar rat model of feeding behavior. Small inhibitions of food intake were also observed in an overnight fasting/refeeding model in SD rats. These data suggest a potential role for Y1R in the regulation of food intake in rodents. 相似文献
15.
Kensuke Kobayashi Tetsuya Kato Izumi Yamamoto Atsushi Shimizu Sayaka Mizutani Masanori Asai Hiroshi Kawamoto Satoru Ito Takashi Yoshizumi Mioko Hirayama Satoshi Ozaki Hisashi Ohta Osamu Okamoto 《Bioorganic & medicinal chemistry letters》2009,19(11):3100-3103
A structure–activity relationship (SAR) study on the benzimidazole series of opioid receptor-like 1 (ORL1) antagonists related to 1 is described. Optimization of 1 by introduction of a hydrophilic substituent into the thioether part resulted in identification of potent ORL1 antagonists with high selectivity over binding affinity for hERG and other opioid receptors. 相似文献
16.
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
17.
Sato N Shibata T Jitsuoka M Ohno T Takahashi T Hirohashi T Kanno T Iwaasa H Kanatani A Fukami T 《Bioorganic & medicinal chemistry letters》2004,14(7):1761-1764
A series of substituted 4-alkoxy-2-aminopyridines 2, which were formally derived from neuropeptide Y1 antagonist 1 by replacing the morpholino portion with alkoxy groups, were synthesized and evaluated as neuropeptide Y Y1 receptor antagonists. Primary structure-activity relationships and identification of potent 4-alkoxy derivatives are described. 相似文献
18.
Nagaaki Sato Makoto Jitsuoka Shiho Ishikawa Keita Nagai Hiroyasu Tsuge Makoto Ando Osamu Okamoto Hisashi Iwaasa Akira Gomori Akane Ishihara Akio Kanatani Takehiro Fukami 《Bioorganic & medicinal chemistry letters》2009,19(6):1670-1674
Novel imidazoline derivatives were discovered to be potent neuropeptide Y Y5 receptor antagonists. High-throughput screening of Merck sample collections against the human Y5 receptor resulted in the identification of 2,4,4-triphenylimidazoline (1), which had an IC50 of 54 nM. Subsequent optimization led to the identification of several potent derivatives. 相似文献
19.
Denise Zwanziger Ilka Böhme Diana Lindner Annette G. Beck‐Sickinger 《Journal of peptide science》2009,15(12):856-866
Selective NPY analogues are potent tools for tumour targeting. Their Y1‐receptors are significantly over‐expressed in human breast tumours, whereas normal breast tissue only expresses Y2‐receptors. The endogenous peptide consists of 36 amino acids, whereas smaller peptides are preferred because of better labelling efficiencies. As Y1‐receptor agonists enhance the tumour to background ratio compared to Y1‐receptor antagonists, we were interested in the development of Y1‐receptor selective agonists. We designed 19 peptides containing the C‐terminus of NPY (28–36) with several modifications. By using competition receptor binding affinity assays, we identified three NPY analogues with high Y1‐receptor affinity and selectivity. Metabolic stability studies in human blood plasma of the N‐terminally 5(6)‐carboxyfluorescein (CF) labelled peptides resulted in half‐lives of several hours. Furthermore, the degradation pattern revealed proteolytic degradation of the peptides by amino peptidases. The most promising peptide was further investigated in receptor activation and internalization studies. Signal transduction assays revealed clear agonistic properties, which could be confirmed by microscopy studies that showed clear Y1‐receptor internalization. For the first time, here we show the design and characterization of a small Y1‐receptor selective agonist. This agonist might be a useful novel ligand for NPY‐mediated tumour diagnostics and therapeutics. Copyright © 2009 European Peptide Society and John Wiley & Sons, Ltd. 相似文献
20.
Gillman KW Higgins MA Poindexter GS Browning M Clarke WJ Flowers S Grace JE Hogan JB McGovern RT Iben LG Mattson GK Ortiz A Rassnick S Russell JW Antal-Zimanyi I 《Bioorganic & medicinal chemistry》2006,14(16):5517-5526
A series of novel 5,5-diphenylimidazolones was synthesized and evaluated for activity against the human neuropeptide Y5 receptor. The 3-pyridyl analog 46 demonstrated an IC(50) of 8.3 nM with a favorable pharmacokinetic profile in rats, but was ineffective in reducing food intake. 相似文献