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Palucki BL Park MK Nargund RP Tang R MacNeil T Weinberg DH Vongs A Rosenblum CI Doss GA Miller RR Stearns RA Peng Q Tamvakopoulos C Van der Ploeg LH Patchett AA 《Bioorganic & medicinal chemistry letters》2005,15(8):1993-1996
We report the discovery and optimization of substituted 2-piperazinecarboxamides as potent and selective agonists of the melanocortin subtype-4 receptor. The 5- and 6-alkylated piperazine compounds exhibit low bioactivation potential as measured by covalent binding in microsome preparations. 相似文献
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Sebhat IK Lai Y Barakat K Ye Z Tang R Kalyani RN Vongs A Macneil T Weinberg DH Cabello MA Maroto M Teran A Fong TM Van der Ploeg LH Patchett AA Nargund RP 《Bioorganic & medicinal chemistry letters》2007,17(20):5720-5723
SAR about the piperidine core in a series of MC4R agonists is described. A number of alkyl substituents that furnish compounds with good affinity and functional potency are reported. 相似文献
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The melanocortin 4 receptor (MC4-R) is a Gs-coupled receptor known to increase cAMP production following agonist stimulation. We demonstrate that the mitogen-activated protein kinases p42 (ERK2) and p44 (ERK1) are also activated by MC4-R following treatment with the MC4-R agonist NDP--MSH in stably transfected CHO-K1 cells. This time- and dose-dependent response is abolished by the MC4-R antagonist SHU-9119. p42/p44 MAPK activation is blocked by the phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and LY294002 but not by the protein kinase A (PKA) inhibitor Rp-cAMPS, indicating that that signal activating the p42/p44 MAPK pathway is conveyed through inositol triphosphate. 相似文献
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Hua V. Lin Dunlu Chen Zhu Shen Lei Zhu Xuesong Ouyang Aurawan Vongs Yanqing Kan John M. Levorse Edward J. Kowalik Jr Daphne M. Szeto Xiaorui Yao Jianying Xiao Shirley Chen Jinqi Liu Marga Garcia-Calvo Myung K. Shin Shirly Pinto 《PloS one》2013,8(1)
Diacylglycerol acyltransferase-1 (DGAT1) is a potential therapeutic target for treatment of obesity and related metabolic diseases. However, the degree of DGAT1 inhibition required for metabolic benefits is unclear. Here we show that partial DGAT1 deficiency in mice suppressed postprandial triglyceridemia, led to elevations in glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) only following meals with very high lipid content, and did not protect from diet-induced obesity. Maximal DGAT1 inhibition led to enhanced GLP-1 and PYY secretion following meals with physiologically relevant lipid content. Finally, combination of DGAT1 inhibition with dipeptidyl-peptidase-4 (DPP-4) inhibition led to further enhancements in active GLP-1 in mice and dogs. The current study suggests that targeting DGAT1 to enhance postprandial gut hormone secretion requires maximal inhibition, and suggests combination with DPP-4i as a potential strategy to develop DGAT1 inhibitors for treatment of metabolic diseases. 相似文献
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Ye Z Guo L Barakat KJ Pollard PG Palucki BL Sebhat IK Bakshi RK Tang R Kalyani RN Vongs A Chen AS Chen HY Rosenblum CI MacNeil T Weinberg DH Peng Q Tamvakopoulos C Miller RR Stearns RA Cashen DE Martin WJ Metzger JM Strack AM MacIntyre DE Van der Ploeg LH Patchett AA Wyvratt MJ Nargund RP 《Bioorganic & medicinal chemistry letters》2005,15(15):3501-3505
A novel isoquinuclidine containing selective melanocortin subtype-4 receptor small molecule agonist, 3 (RY764), is reported. Its in vivo characterization revealed mechanism-based food intake reduction and erectile activity augmentation in rodents. 相似文献
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Jeffrey P. Varnerin Timothy Smith Charles I. Rosenblum Aurawan Vongs Beth A. Murphy Chris Nunes Theodore N. Mellin Joseph J. King Bruce W. Burgess Beth Junker Michael Chou Patricia Hey Easter Frazier D.Euan MacIntyre Lex H.T. Van der Ploeg Michael R. Tota 《Protein expression and purification》1998,14(3):335-342
A procedure is described for gram-scale refolding ofEscherichia coli-derived human leptin inclusion bodies. Refolding was achieved by gradually reducing denaturant using a diafiltration method. Refolded leptin is characterized byin vivomodulation of food intake, reduction in body weight, and lowering of insulin and glucose levels inob/obmice. In addition, refolded leptin is characterized by radioimmunoassay (RIA) and activation of the leptin receptor in a cell-based assay. For comparison we also refolded leptin by a simple dilution method and produced periplasmic derived leptin, which did not requireex vivofolding. Leptin produced by these three methods and leptin obtained from commercial sources were compared using the RIA and the cell-based assay and appeared to be of comparable quality and potency. 相似文献
7.
In an effort to learn more about the genomic organization of chromosomal termini in plants we employed a functional complementation strategy to isolate Arabidopsis thaliana telomeres in the yeast, Saccharomyces cerevisiae. Eight yeast episomes carrying A. thaliana telomeric sequences were obtained. The plant sequences carried on two episomes, YpAtT1 and YpAtT7, were characterized in detail. The telomeric origins of YpAtT1 and YpAtT7 insert DNAs were confirmed by demonstrating that corresponding genomic sequences are preferentially degraded during exonucleolytic digestion. The isolated telomeric restriction fragments contain G-rich repeat arrays characteristic of A. thaliana telomeres, as well as subterminal telomere-associated sequences (TASs). DNA sequence analysis revealed the presence of variant telomeric repeats at the centromere-proximal border of the terminal block of telomere repeats. The TAS flanking the telomeric G-rich repeat in YpAtT7 corresponds to a repetitive element present at other A. thaliana telomeres, while more proximal sequences are unique to one telomere. The YpAtT1 TAS is unique in the Landsberg strain of A. thaliana from which the clone originated; however, the Landsberg TAS cross-hybridizes weakly to a second telomere in the strain Columbia. Restriction analysis with cytosine methylation-sensitive endonucleases indicated that both TASs are highly methylated in the genome. 相似文献
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Ujjainwalla F Warner D Walsh TF Wyvratt MJ Zhou C Yang L Kalyani RN MacNeil T Van der Ploeg LH Rosenblum CI Tang R Vongs A Weinberg DH Goulet MT 《Bioorganic & medicinal chemistry letters》2003,13(24):4431-4435
The discovery and optimization of a new class of non-peptidyl, pyridazinone derived melanocortin subtype-4 receptor agonists is disclosed. 相似文献
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Palucki BL Park MK Nargund RP Ye Z Sebhat IK Pollard PG Kalyani RN Tang R Macneil T Weinberg DH Vongs A Rosenblum CI Doss GA Miller RR Stearns RA Peng Q Tamvakopoulos C McGowan E Martin WJ Metzger JM Shepherd CA Strack AM Macintyre DE Van der Ploeg LH Patchett AA 《Bioorganic & medicinal chemistry letters》2005,15(1):171-175
We report the discovery and optimization of substituted 2-piperazinecarboxamides as potent and selective agonists of the melanocortin subtype-4 receptor. Further in vivo development of lead agonist, MB243, is disclosed. 相似文献
10.
Qingmei Hong Raman K. Bakshi James Dellureficio Shuwen He Zhixiong Ye Peter H. Dobbelaar Iyassu K. Sebhat Liangqin Guo Jian Liu Tianying Jian Rui Tang Rubana N. Kalyani Tanya MacNeil Aurawan Vongs Charles I. Rosenblum David H. Weinberg Qingping Peng Constantin Tamvakopoulos Randy R. Miller Ralph A. Stearns Ravi P. Nargund 《Bioorganic & medicinal chemistry letters》2010,20(15):4483-4486
Design, syntheses and structure–activity relationships of N-acetylated piperazine privileged structures containing MC4R agonist compounds were described. The most potent derivatives were low nM MC4R selective full agonists. Several compounds from the series had modest pharmacokinetic properties. 相似文献
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