共查询到20条相似文献,搜索用时 46 毫秒
1.
Shuwen He Zhixiong Ye Peter H. Dobbelaar Iyassu K. Sebhat Liangqin Guo Jian Liu Tianying Jian Yingjie Lai Christopher L. Franklin Raman K. Bakshi James P. Dellureficio Qingmei Hong David H. Weinberg Tanya MacNeil Rui Tang Alison M. Strack Constantin Tamvakopoulos Qianping Peng Randy R. Miller Ralph A. Stearns Ravi P. Nargund 《Bioorganic & medicinal chemistry letters》2010,20(15):4399-4405
We report a series of potent and selective MC4R agonists based on spiroindane amide privileged structures for potential treatments of obesity. Among the synthetic methods used, Method C allows rapid synthesis of the analogs. The series of compounds can afford high potency on MC4R as well as good rodent pharmacokinetic profiles. Compound 1r (MK-0489) demonstrates MC4R mediated reduction of food intake and body weight in mouse models. Compound 1r is efficacious in 14-day diet-induced obese (DIO) rat models. 相似文献
2.
Pontillo J Tran JA Fleck BA Marinkovic D Arellano M Tucci FC Lanier M Nelson J Parker J Saunders J Murphy B Foster AC Chen C 《Bioorganic & medicinal chemistry letters》2004,14(22):5605-5609
SAR studies of a series of piperazinebenzylamines resulted in the discovery of potent antagonists of the human melanocortin-4 receptor. Compounds 11c, 11d, and 11l, which had K(i) values of 21, 14, and 15 nM, respectively, possessed low efficacy in cAMP stimulation ( approximately 15% of alpha-MSH maximal level) mediated by MC4R, and functioned as antagonists in inhibition of alpha-MSH-stimulated cAMP release in a dose-dependent manner (11l, IC(50)=36 nM). 相似文献
3.
Tran JA Pontillo J Arellano M Fleck BA Tucci FC Marinkovic D Chen CW Saunders J Foster AC Chen C 《Bioorganic & medicinal chemistry letters》2005,15(14):3434-3438
A series of cyclohexylpiperazines was synthesized as potent and selective antagonists of the human MC4 receptor. Compound 14t displayed binding affinity (Ki) of 4.2 and 1100 nM at MC4R and MC3R, respectively. 相似文献
4.
Pontillo J Tran JA Markison S Joppa M Fleck BA Marinkovic D Arellano M Tucci FC Lanier M Nelson J Saunders J Hoare SR Foster AC Chen C 《Bioorganic & medicinal chemistry letters》2005,15(10):2541-2546
Optimization on a series of piperazinebenzylamines resulted in analogues with low nanomolar binding at the human MC4 receptor but weak affinity (Ki > 500 nM) at the MC3 receptor. Compound 14c was identified to be a potent MC4R antagonist (Ki = 3.2 nM) with a selectivity of 240-fold over MC3R. It proved to be an insurmountable antagonist in a cAMP assay. Compound 14c potently stimulated food intake in satiated mice when given by intracerebroventricular administration. 相似文献
5.
Chen CW Tran JA Fleck BA Tucci FC Jiang W Chen C 《Bioorganic & medicinal chemistry letters》2007,17(24):6825-6831
A series of trans-N-alkyl-4-(4-chlorophenyl)pyrrolidine-3-carboxamides of piperazinecyclohexanemethylamines was synthesized and characterized for binding and function at the melanocortin-4 receptor (MC4R), and several potent benzylamine derivatives were identified. Compound 18v was found to bind MC4R with potent affinity (Ki = 0.5 nM) and high selectivity over the other melanocortin subtypes and behaved as a functional antagonist (IC50 = 48 nM). 相似文献
6.
Koikov LN Ebetino FH Hayes JC Cross-Doersen D Knittel JJ 《Bioorganic & medicinal chemistry letters》2004,14(19):4839-4842
Of the 42 R'-X-(p-Cl)Phe-D-Phe-Arg-Trp-NH(2) (X=CO, SO(2), PO, PS) tested at the human (h)MC1, hMC3, and hMC4 receptors (R), the most potent MC4R agonists (EC(50) of 8-20 nM) were obtained by end-capping with R'=CH(2)CHCH(2) (9), NCCH(2) (16), NH(2)COCH(2) (17), HCONHCH(2) (18), CH(3)NH (19), CH(2)CHCH(2)NH (21), 2-Th (23), PhCH(2) (30) and X=CO. These compounds possess 35-60-fold hMC4 versus hMC1Rs selectivity with urea LK-71 (19) being the most potent at hMC4R and MC4/1R selective (EC(50)=8.5 nM, MC4/1R=100). LK-75 (16) combines high potency at hMC4R and MC4/3R selectivity (EC(50)=10.5 nM, MC4/3R=290). SAR is discussed. 相似文献
7.
8.
Tucci FC White NS Markison S Joppa M Tran JA Fleck BA Madan A Dyck BP Parker J Pontillo J Arellano LM Marinkovic D Jiang W Chen CW Gogas KR Goodfellow VS Saunders J Foster AC Chen C 《Bioorganic & medicinal chemistry letters》2005,15(19):4389-4395
The melanocortin-4 receptor (MC4R) plays an important role in the regulation of energy homeostasis. Recent studies have shown that blockade of the MC4R reverses tumor-induced weight loss in mice. Herein, we describe the synthesis and identification of potent and selective non-peptide antagonists of the human MC4R from a series of 2-ethoxycarbonylcyclohexyl-piperazines. Compound 12i was found to possess low nanomolar affinity for the MC4R, and exhibit oral bioavailability in rats. More importantly, when administered orally to mice (10 mg/kg), it led to statistically significant increases in food intake over a 24-h period. 相似文献
9.
Hong Q Bakshi RK Palucki BL Park MK Ye Z He S Pollard PG Sebhat IK Liu J Guo L Cashen DE Martin WJ Weinberg DH MacNeil T Tang R Tamvakopoulos C Peng Q Miller RR Stearns RA Chen HY Chen AS Strack AM Fong TM MacIntyre DE Wyvratt MJ Nargund RP 《Bioorganic & medicinal chemistry letters》2011,21(8):2330-2334
We report the discovery of piperazine urea based compound 1, a potent, selective, orally bioavailable melanocortin subtype-4 receptor partial agonist. Compound 1 shows anti-obesity efficacy without potentiating erectile activity in the rodent models. 相似文献
10.
Seko T Kato M Kohno H Ono S Hashimura K Takimizu H Nakai K Maegawa H Katsube N Toda M 《Bioorganic & medicinal chemistry letters》2001,11(16):2067-2070
The synthesis and structure-activity relationship (SAR) study of a novel series of N-type calcium channel blockers are described. L-Cysteine derivative 2a was found to be a potent and selective N-type calcium channel blocker with IC(50) 0.63 microM on IMR-32 assay. Compound 2a showed analgesic efficacy in the rat formalin-induced pain model by intrathecal and oral administration. 相似文献
11.
Liangqin Guo Zhixiong Ye Jian Liu Shuwen He Raman K. Bakshi Iyassu K. Sebhat Peter H. Dobbelaar Qingmei Hong Tianying Jian James P. Dellureficio Nancy N. Tsou Richard G. Ball David H. Weinberg Tanya MacNeil Rui Tang Constantin Tamvakopoulos Qianping Peng Howard Y. Chen Airu S. Chen William J. Martin Ravi P. Nargund 《Bioorganic & medicinal chemistry letters》2010,20(16):4895-4900
Design, synthesis, and SAR of a series of 3H-spiro[isobenzofuran-1,4′-piperidine] based compounds as potent, selective and orally bioavailable melanocortin subtype-4 receptor (MC4R) agonists are disclosed. 相似文献
12.
MacKenzie RG 《Peptides》2006,27(2):395-403
Mutations in the human melanocortin-4 receptor (MC4R) gene have been associated with severe obesity. Many of the mutations result in partial or complete loss-of-function based on the nature of the mutation or the function of mutated receptors when tested in heterologous expression systems. This review discusses the role of MC4R in the central regulation of body weight, the pathogenic mechanisms of the mutations, and the validity of MC4R as an anti-obesity drug target. 相似文献
13.
Melanocortin subtype-4 receptor agonists containing a piperazine core with substituted aryl sulfonamides 总被引:1,自引:0,他引:1
Fotsch C Han N Arasasingham P Bo Y Carmouche M Chen N Davis J Goldberg MH Hale C Hsieh FY Kelly MG Liu Q Norman MH Smith DM Stec M Tamayo N Xi N Xu S Bannon AW Baumgartner JW 《Bioorganic & medicinal chemistry letters》2005,15(6):1623-1627
The biological activity for a set of melanocortin-4 receptor (MC4R) agonists containing a piperazine core with an ortho-substituted aryl sulfonamide is described. Compounds from this set had binding and functional activities at MC4R less than 30 nM. The most selective compound in this series was >25,000-fold more potent at MC4R than MC3R, and 490-fold more potent at MC4R than MC5R. This compound also reduced food intake after oral dosing at 25, 50, and 100 mg kg(-1) in fasted mice. 相似文献
14.
Watterson SH Langevine CM Van Kirk K Kempson J Guo J Spergel SH Das J Moquin RV Dyckman AJ Nirschl D Gregor K Pattoli MA Yang X McIntyre KW Yang G Galella MA Booth-Lute H Chen L Yang Z Wang-Iverson D McKinnon M Dodd JH Barrish JC Burke JR Pitts WJ 《Bioorganic & medicinal chemistry letters》2011,21(23):7006-7012
The synthesis, structure-activity relationships (SAR), and biological results of pyridyl-substituted azaindole based tricyclic inhibitors of IKK2 are described. Compound 4m demonstrated potent in vitro potency, acceptable pharmacokinetic and physicochemical properties, and efficacy when dosed orally in a mouse model of inflammatory bowel disease. 相似文献
15.
Fotsch C Smith DM Adams JA Cheetham J Croghan M Doherty EM Hale C Jarosinski MA Kelly MG Norman MH Tamayo NA Xi N Baumgartner JW 《Bioorganic & medicinal chemistry letters》2003,13(14):2337-2340
The solution structure of a potent melanocortin receptor agonist, Ac-Nle-cyclo[Asp-Pro-DPhe-Arg-Trp-Lys]-NH(2) (1) was calculated using distance restraints determined from 1H NMR spectroscopy. Eight of the lowest energy conformations from this study were used to identify non-peptide cores that mimic the spatial arrangement of the critical tripeptide region, DPhe-Arg-Trp, found in 1. From these studies, compound 2a, containing the cis-cyclohexyl core, was identified as a functional agonist of the melanocortin-4 receptor (MC4R) with an IC(50) and EC(50) below 10 nM. Compound 2a also showed 36- and 7-fold selectivity over MC3R and MC1R, respectively, in the binding assays. Subtle changes in cyclohexane stereochemistry and removal of functional groups led to analogues with lower affinity for the MC receptors. 相似文献
16.
Pontillo J Marinkovic D Tran JA Arellano M Fleck BA Wen J Tucci FC Nelson J Saunders J Foster AC Chen C 《Bioorganic & medicinal chemistry letters》2005,15(20):4615-4618
Piperazinebenzylamines bearing a small N-(1-methoxy-2-propyl) side chain were found to be potent and selective antagonists of the human melanocortin-4 (MC4) receptor. Compound 7b, having K(i) values of 6.9 and 2800 nM at the human MC4 and MC3 receptors, respectively, has moderate oral bioavailability in mice, which is improved relative to the arylethyl analogues. 相似文献
17.
Clasby MC Chackalamannil S Czarniecki M Doller D Eagen K Greenlee WJ Lin Y Tsai H Xia Y Ahn HS Agans-Fantuzzi J Boykow G Chintala M Foster C Bryant M Lau J 《Bioorganic & medicinal chemistry letters》2006,16(6):1544-1548
The design, synthesis, and SAR studies of a structurally novel series of highly potent thrombin receptor (PAR-1) antagonists are described. Compound 30 is a highly potent thrombin receptor antagonist (IC(50)=6.3 nM), a related compound 36 showing efficacy in a monkey ex vivo study. 相似文献
18.
Xiong Y Wiltsie J Woods A Guo J Pivnichny JV Tang W Bansal A Cummings RT Cunningham BR Friedlander AM Douglas CM Salowe SP Zaller DM Scolnick EM Schmatz DM Bartizal K Hermes JD MacCoss M Chapman KT 《Bioorganic & medicinal chemistry letters》2006,16(4):964-968
A potent and selective anthrax LF inhibitor 40, (2R)-2-[(4-fluoro-3-methylphenyl)sulfonylamino]-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide, was identified through SAR study of a high throughput screen lead. It has an IC50 of 54 nM in the enzyme assay and an IC50 of 210 nM in the macrophage cytotoxicity assay. Compound 40 is also effective in vivo in several animal model studies. 相似文献
19.
We have investigated receptor structural components of the melanocortin-4 receptor (MC4R) responsible for ligand-dependent inverse agonism. We utilized agouti-related protein (AGRP), an inverse agonist which reduces MC4R basal cAMP production, as a tool to determine the molecular mechanism. We tested a series of chimeric receptors and utilized MC4R and MC1R as templates, in which AGRP is an inverse agonist for MC4R but not for MC1R. Our results indicate that replacements of the extracellular loops 1, 2 and 3 of MC4R with the corresponding regions of MC1R did not affect AGRP inverse agonist activity. However, replacement of the N terminus of MC4R with the same region of MC1R decreases AGRP inverse agonism. Replacement of transmembrane domains 3, 4, 5 and 6 of MC4R with the corresponding regions of MC1R did not affect AGRP inverse agonist activity but mutation of D90A in transmembrane 2 (TM2) and D298A in TM7 abolished AGRP inverse activity. Deletion of the distal MC4R C terminus fails to maintain AGRP mediated reduction in basal cAMP production although it maintains NDP-MSH mediated cAMP production. In conclusion, our results indicate that the N terminus and the distal C terminus of MC4R do appear to play important roles in AGRP inverse agonism but not NDP-MSH mediated receptor activation. Our results also indicate that the residues D90 in TM2 and D298 in TM7 of hMC4R are involved in not only NDP-MSH mediated receptor activation but also AGRP mediated inverse agonism. 相似文献
20.
Nicolas A. Heyder Gunnar Kleinau David Speck Andrea Schmidt Sarah Paisdzior Michal Szczepek Brian Bauer Anja Koch Monique Gallandi Dennis Kwiatkowski Jrg Bürger Thorsten Mielke Annette G. Beck-Sickinger Peter W. Hildebrand Christian M. T. Spahn Daniel Hilger Magdalena Schacherl Heike Biebermann Tarek Hilal Peter Kühnen Brian K. Kobilka Patrick Scheerer 《Cell research》2021,31(11):1176
The melanocortin-4 receptor (MC4R), a hypothalamic master regulator of energy homeostasis and appetite, is a class A G-protein-coupled receptor and a prime target for the pharmacological treatment of obesity. Here, we present cryo-electron microscopy structures of MC4R–Gs-protein complexes with two drugs recently approved by the FDA, the peptide agonists NDP-α-MSH and setmelanotide, with 2.9 Å and 2.6 Å resolution. Together with signaling data from structure-derived MC4R mutants, the complex structures reveal the agonist-induced origin of transmembrane helix (TM) 6-regulated receptor activation. The ligand-binding modes of NDP-α-MSH, a high-affinity linear variant of the endogenous agonist α-MSH, and setmelanotide, a cyclic anti-obesity drug with biased signaling toward Gq/11, underline the key role of TM3 in ligand-specific interactions and of calcium ion as a ligand-adaptable cofactor. The agonist-specific TM3 interplay subsequently impacts receptor–Gs-protein interfaces at intracellular loop 2, which also regulates the G-protein coupling profile of this promiscuous receptor. Finally, our structures reveal mechanistic details of MC4R activation/inhibition, and provide important insights into the regulation of the receptor signaling profile which will facilitate the development of tailored anti-obesity drugs.Subject terms: Cryoelectron microscopy, Cell signalling 相似文献