共查询到20条相似文献,搜索用时 0 毫秒
1.
Epple R Russo R Azimioara M Cow C Xie Y Wang X Wityak J Karanewsky D Gerken A Iskandar M Saez E Martin Seidel H Tian SS 《Bioorganic & medicinal chemistry letters》2006,16(16):4376-4380
We report the identification of a novel series of trisubstituted isoxazoles as PPAR activators from a high-throughput screen. A series of structural optimizations led to improved efficacy and excellent functional receptor selectivity for PPARdelta. The isoxazoles represent a series of agonists which display a scaffold that lies outside the typical PPAR agonist motif. 相似文献
2.
Epple R Azimioara M Russo R Xie Y Wang X Cow C Wityak J Karanewsky D Bursulaya B Kreusch A Tuntland T Gerken A Iskandar M Saez E Martin Seidel H Tian SS 《Bioorganic & medicinal chemistry letters》2006,16(21):5488-5492
A series of PPARdelta-selective agonists was investigated and optimized for a favorable in vivo pharmacokinetic profile. Isoxazole LCI765 (17d) was found to be a potent and selective PPARdelta agonist with good in vivo PK properties in mouse (C(max)=5.1 microM, t(1/2)=3.1 h). LCI765 regulated expression of genes involved in energy homeostasis in relevant tissues when dosed orally in C57BL6 mice. A co-crystal structure of compound LCI765 and the LBD of PPARdelta is discussed. 相似文献
3.
Zhang R Wang A DeAngelis A Pelton P Xu J Zhu P Zhou L Demarest K Murray WV Kuo GH 《Bioorganic & medicinal chemistry letters》2007,17(14):3855-3859
A novel series of potent and selective PPARdelta agonists, para-alkylthiophenoxyacetic acids, was identified. The synthesis and structure-activity relationships are described. 相似文献
4.
Havranek M Sauerberg P Mogensen JP Kratina P Jeppesen CB Pettersson I Pihera P 《Bioorganic & medicinal chemistry letters》2007,17(15):4144-4149
Y-shaped molecules bearing alkynylallylic moieties were found to be potent and selective PPARdelta activators. The alkynylallylic moiety was synthesized from alkyn-1-ols by hydroalumination followed by a cross-coupling reaction. Series of active compounds 6 were obtained by stepwise changing the structure of the known PPARpan agonist 5 into Y-shaped compounds. The most active and selective compound, 6f, had a PPARdelta potency of 0.13 microM, which is 50-fold more potent than compound 5. 相似文献
5.
Adams AD Hu Z von Langen D Dadiz A Elbrecht A MacNaul KL Berger JP Zhou G Doebber TW Meurer R Forrest MJ Moller DE Jones AB 《Bioorganic & medicinal chemistry letters》2003,13(19):3185-3190
A new class of O-arylmandelic acid PPAR agonists show excellent anti-hyperglycemic efficacy in a db/db mouse model of DM2. These PPARalpha-weighted agonists do not show the typical PPARgamma associated side effects of BAT proliferation and cardiac hypertrophy in a rat tolerability assay. 相似文献
6.
AMPK and PPARdelta agonists are exercise mimetics 总被引:1,自引:0,他引:1
Narkar VA Downes M Yu RT Embler E Wang YX Banayo E Mihaylova MM Nelson MC Zou Y Juguilon H Kang H Shaw RJ Evans RM 《Cell》2008,134(3):405-415
The benefits of endurance exercise on general health make it desirable to identify orally active agents that would mimic or potentiate the effects of exercise to treat metabolic diseases. Although certain natural compounds, such as reseveratrol, have endurance-enhancing activities, their exact metabolic targets remain elusive. We therefore tested the effect of pathway-specific drugs on endurance capacities of mice in a treadmill running test. We found that PPARbeta/delta agonist and exercise training synergistically increase oxidative myofibers and running endurance in adult mice. Because training activates AMPK and PGC1alpha, we then tested whether the orally active AMPK agonist AICAR might be sufficient to overcome the exercise requirement. Unexpectedly, even in sedentary mice, 4 weeks of AICAR treatment alone induced metabolic genes and enhanced running endurance by 44%. These results demonstrate that AMPK-PPARdelta pathway can be targeted by orally active drugs to enhance training adaptation or even to increase endurance without exercise. 相似文献
7.
Weigand S Bischoff H Dittrich-Wengenroth E Heckroth H Lang D Vaupel A Woltering M 《Bioorganic & medicinal chemistry letters》2005,15(20):4619-4623
We report the solid-phase synthesis and pharmacological evaluation of a new series of small-molecule agonists of the human peroxisome proliferator-activated receptor delta (PPARdelta) based on a lead structure from our PPARalpha program. Compound 33 showed good pharmacokinetics. 相似文献
8.
Slassi A Edwards L O'Brien A Meng CQ Xin T Seto C Lee DK MacLean N Hynd D Chen C Wang H Kamboj R Rakhit S 《Bioorganic & medicinal chemistry letters》2000,10(15):1707-1709
A series of 5-alkyltryptamines (6) and the corresponding conformationally constrained analogues (8) have been synthesized. The structure activity relationships (SAR) at the 5-position of the indole skeleton and the ethylamine side chain have been studied. Functional activities were assessed using isolated rabbit saphenous vein. Potent, selective ligands were found (6e, Ki 2.5 nM, 5-HT1B/5-HT1D 125-fold) that have potential for treating acute migraine. 相似文献
9.
Novel selective small molecule agonists for peroxisome proliferator-activated receptor delta (PPARdelta)--synthesis and biological activity 总被引:4,自引:0,他引:4
Sznaidman ML Haffner CD Maloney PR Fivush A Chao E Goreham D Sierra ML LeGrumelec C Xu HE Montana VG Lambert MH Willson TM Oliver WR Sternbach DD 《Bioorganic & medicinal chemistry letters》2003,13(9):1517-1521
We report the synthesis and biological activity of a new series of small molecule agonists of the human Peroxisome Proliferator-Activated Receptor delta (PPARdelta). Several hits were identified from our original libraries containing lipophilic carboxylic acids. Optimization of these hits by structure-guided design led to 7k (GW501516) and 7l (GW0742), which shows an EC(50) of 1.1 nM against PPARdelta with 1000-fold selectivity over the other human subtypes. 相似文献
10.
Shearer BG Patel HS Billin AN Way JM Winegar DA Lambert MH Xu RX Leesnitzer LM Merrihew RV Huet S Willson TM 《Bioorganic & medicinal chemistry letters》2008,18(18):5018-5022
Anthranilic acid GW9371 was identified as a novel class of PPARdelta partial agonist through high-throughput screening. The design and synthesis of SAR analogues is described. GSK1115 and GSK7227 show potent partial agonism of the PPARdelta target genes CPT1a and PDK4 in skeletal muscle cells. 相似文献
11.
Carling RW Russell MG Moore KW Mitchinson A Guiblin A Smith A Wafford KA Marshall G Atack JR Street LJ 《Bioorganic & medicinal chemistry letters》2006,16(13):3550-3554
Novel synthetic routes have been devised for the preparation of previously inaccessible 2,3,7-trisubstituted pyrazolo[1,5-d][1,2,4]triazines 2. These compounds are high affinity ligands for the GABA(A) benzodiazepine binding site and some analogues show functional selectivity for agonism at alpha3-containing receptors over alpha1-containing receptors with the lead compound being 32. 相似文献
12.
Parker DL Meng D Ratcliffe RW Wilkening RR Sperbeck DM Greenlee ML Colwell LF Lambert S Birzin ET Frisch K Rohrer SP Nilsson S Thorsell AG Hammond ML 《Bioorganic & medicinal chemistry letters》2006,16(17):4652-4656
Several tetrahydrofluorenones with a triazole fused across C7-C8 showed high levels of ERbeta-selectivity and were found to be potent ERbeta-agonists. As a class they demonstrate improved oral bioavailability in the rat over a parent class of 7-hydroxy-tetrahydrofluorenones. The most selective agonist displayed 5.7 nM affinity and 333-fold selectivity for ERbeta. 相似文献
13.
Verbist BM De Cleyn MA Surkyn M Fraiponts E Aerssens J Nijsen MJ Gijsen HJ 《Bioorganic & medicinal chemistry letters》2008,18(8):2574-2579
A novel series of benzimidazole CB2-receptor agonists was synthesized and the structure-activity relationship explored. The results showed agonistic activities with an EC(50) up to 0.5 nM and excellent selectivity (>4000-fold) over the CB1 receptor. The size of the substituent on the 2-position determined the level of agonism, ranging from inverse agonism to partial agonism to full agonism, which was more pronounced for the rat CB2 receptor. A wide variation of sulfonyl substituents at the benzimidazole 5-position was tolerated, which was used to optimize the drug-like properties. This resulted into lead compound 14j that can be used to investigate the potential of a selective, peripherically acting CB2 agonist. The in vitro profile of key compounds is displayed using pie bar charts (VlaaiVis). 相似文献
14.
Teymour Vahedpour Jatinder Kaur Salar Hemmati Maryam Hamzeh-Mivehroud Ali Akbar Alizadeh Frank Wuest Siavoush Dastmalchi 《化学与生物多样性》2021,18(3):e2000832
A new series of 1,3,5-trisubstituted 2-pyrazolines for the inhibition of cyclooxygenase-2 (COX-2) were synthesized. The designed structures include a COX-2 pharmacophore SO2CH3 at the para-position of the phenyl ring located at C-5 of a pyrazoline scaffold. The synthesized compounds were tested for in vitro COX-1/COX-2 inhibition and cell toxicity against human colorectal adenocarcinoma cell lines HT-29. The lead compound (4-chlorophenyl){5-[4-(methanesulfonyl)phenyl]-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl}methanone ( 16 ) showed significant COX-2 inhibition (IC50=0.05±0.01 μM), and antiproliferative activity (IC50=5.46±4.71 μM). Molecular docking studies showed that new pyrazoline-based compounds interact via multiple hydrophobic and hydrogen-bond interactions with key binding site residues of the COX-2 enzyme. 相似文献
15.
Lee HW Shin DH Jeong JY Kim HO Chun MW Melman N Gao ZG Jacobson KA Jeong LS 《Nucleosides, nucleotides & nucleic acids》2005,24(5-7):607-609
4'-Thionucleoside derivatives as potent and selective A3 adenosaine receptor agonists were synthesized, starting from D-gulono-gamma-lactone via D-thioribosyl acetate as a key intermediate, among which the 2-chloro-N6-methyladenosine-5-methyluronamide showed the most potent and selective binding affinity (Ki = 0.28 +/- 0.09 nM) at the human A3 adenosine receptor. 相似文献
16.
Chesworth R Zawistoski MP Lefker BA Cameron KO Day RF Mangano FM Rosati RL Colella S Petersen DN Brault A Lu B Pan LC Perry P Ng O Castleberry TA Owen TA Brown TA Thompson DD DaSilva-Jardine P 《Bioorganic & medicinal chemistry letters》2004,14(11):2729-2733
Two series of 6-hydroxy and 7-hydroxy tetrahydroisoquinolines were prepared. Evaluating a range of C-1, C-4, and N-substituents led to the discovery of ER alpha and ER beta selective analogs. 相似文献
17.
Pagé D Balaux E Boisvert L Liu Z Milburn C Tremblay M Wei Z Woo S Luo X Cheng YX Yang H Srivastava S Zhou F Brown W Tomaszewski M Walpole C Hodzic L St-Onge S Godbout C Salois D Payza K Payza K 《Bioorganic & medicinal chemistry letters》2008,18(13):3695-3700
The preparation and evaluation of a novel class of CB2 agonists based on a benzimidazole moiety are reported. They showed binding affinities up to 1nM towards the CB2 receptor with partial to full agonist potencies. They also demonstrated good to excellent selectivity (>1000-fold) over the CB1 receptor. 相似文献
18.
《Bioorganic & medicinal chemistry letters》2014,24(20):4807-4811
The discovery of a new series of selective S1P1 agonists is described. This series of piperazinyl-oxadiazole derivatives was rapidly optimized starting from high-throughput screening hit 1 to afford potent and selective lead compound 10d. Further SAR studies showed that 10d was converted to the active phosphate metabolite 29 in vivo. Oral administration of compound 10d to rats was shown to induce lymphopenia at 3 mg/kg. 相似文献
19.
Stefan Jaroch Markus Berger Christoph Huwe Konrad Krolikiewicz Hartmut Rehwinkel Heike Schäcke Norbert Schmees Werner Skuballa 《Bioorganic & medicinal chemistry letters》2010,20(19):5835-5838
The dissociated glucocorticoid receptor (GR) agonist ZK 216348 is rendered GR-selective over other nuclear hormone receptors through replacing the methylbenzoxazine with a quinoline moiety. Compounds were shown to be efficacious in cell assays with respect to inflammation endpoints, along with reduced activity in a transactivation assay, hinting at an improved therapeutic window over corticosteroids. 相似文献
20.
Stoytcho Stoev Ling Ling Cheng Maurice Manning Nga Ching Wo Hazel H Szeto 《Journal of peptide science》2006,12(9):592-604
We report here the solid-phase synthesis and vasodepressor potencies of a new lead vasopressin (VP) hypotensive peptide [1(beta-mercapto-beta,beta-pentamethylenepropionic acid)-2-0-ethyl-D-tyrosine, 3-arginine, 4-valine, 7-lysine, 9-ethylenediamine] lysine vasopressin, d(CH(2))(5)[D-Tyr(Et)(2), Arg(3), Val(4), Lys(7), Eda(9)]LVP (C) and 21 analogues of C with single modifications at positions 9 (1-13), 6 (14), 2 (16-20) and combined modifications at positions 6 and 10 (15) and 2 and 10 (21). Peptides 1-13 have the following replacements for the Eda residue at position 9 in C: (1) Gly-NH(2); (2) Gly-NH-CH(3); (3) Ala-NH(2); (4) Ala-NH-CH(3), (5) Val-NH(2); (6) Cha-NH(2); (7) Thr-NH(2); (8) Phe-NH(2); (9) Tyr-NH(2); (10) Orn-NH(2); (11) Lys-NH(2); (12) D-Lys-NH(2); (13) Arg-NH(2). Peptide 14 has the Cys residue at position 6 replaced by Pen. Peptide 15 is the retro-Tyr(10) analogue of peptide 14. Peptides 16-20 have the D-Tyr(Et) residue at position 2 in C replaced by the following substituents: D-Trp (16); D-2-Nal (17); D-Tyr(Bu(t))(18); D-Tyr(Pr(n)) (19); D-Tyr(Pr(i)) (20). Peptide 21 is the retro-Tyr(10) analogue of peptide 20. C and peptides 1-21 were evaluated for agonistic and antagonistic activities in in vivo vasopressor (V(1a)-receptor), antidiuretic (V(2)-receptor), and in in vitro (no Mg(2+)) oxytocic (OT-receptor) assays in the rat, and, like the original hypotensive peptide, d(CH(2))(5)[D-Tyr(Et)(2), Arg(3), Val(4)]AVP (A) (Manning et al., J. Peptide Science 1999, 5:472-490), were found to exhibit no or negligible activities in these assays. Vasodepressor potencies were determined in anesthetized male rats with baseline mean arterial blood pressure (BP) maintained at 100-120 mmHg. The effective dose (ED), in microg/100 g i.v., the dose required to produce a vasodepressor response of 5 cm(2) area under the vasodepressor response curve (AUC) during the 5-min period following the injection of the test peptide, was determined. The EDs measure the vasodepressor potencies of the hypotensive peptides C and 1-21 relative to that of A (ED = 4.66 microg/100 g) and to each other. The following ED values in microg/100 g were obtained for C and for peptides 1-21; C 0.53; (1) 2.41; (2) 1.13; (3) 1.62; (4) 0.80; (5) 1.83; (6) 1.56; (7) 2.12, (8) 2.58; (9) 1.40; (10) 0.88; (11) 0.90; (12) 0.85; (13) 0.68; (14) 0.99; (15) 1.05; (16) 0.66; (17) 0.54; (18) 0.33; (19) 0.18; (20) 0.15; (21) 0.14. All of the hypotensive peptides reported here are more potent than A. Peptides 20 and 21 exhibit a striking 30-fold enhancement in vasodepressor potencies relative to A. With a vasodepressor ED = 0.14, peptide 21 is the most potent VP vasodepressor agonist reported to date. Because it contains a retro-Tyr(10) residue, it is a promising new radioiodinatable ligand for the putative VP vasodilating receptor. Some of these new hypotensive peptides may be of value as research tools for studies on the complex cardiovascular actions of VP and may lead to the development of a new class of antihypertensive agents. 相似文献