共查询到20条相似文献,搜索用时 15 毫秒
1.
Pingali H Jain M Shah S Patil P Makadia P Zaware P Sairam KV Jamili J Goel A Patel M Patel P 《Bioorganic & medicinal chemistry letters》2008,18(24):6471-6475
Oxazole containing glycine and oximinobutyric acid derivatives were synthesized as PPARalpha agonists by incorporating polymethylene spacer as a replacement of commonly used phenylene group that connects the acidic head with lipophilic tail. Compound 13a was found to be a selective and potent PPARalpha agonist. Further 1,3-dioxane-2-carboxylic acid derivative 20 was synthesized by replacing the tetramethylene spacer of NS-220, a selective PPARalpha agonist with phenylene group and found to exhibit PPARalpha/gamma dual agonism. These results suggest that compounds possessing polymethylene spacer between pharmacophore and lipophilic tail exhibit predominantly PPARalpha agonism whereas those with an aromatic phenylene spacer shows PPARalpha/gamma dual agonism. 相似文献
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Kim NJ Lee KO Koo BW Li F Yoo JK Park HJ Min KH Lim JI Kim MK Kim JK Suh YG 《Bioorganic & medicinal chemistry letters》2007,17(13):3595-3598
We have developed a new class of PPARalpha/gamma dual agonists, which show excellent agonistic activity in PPARalpha/gamma transactivation assay. In particular, (R)-9d was identified as a potent PPARalpha/gamma dual agonist with EC(50)s of 0.377 microM in PPARalpha and 0.136 microM in PPARgamma, respectively. Interestingly, the structure-activity relationship revealed that the stereochemistry of the identified PPARalpha/gamma dual agonists significantly affects their agonistic activities in PPARalpha than in PPARgamma. 相似文献
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Oon Han H Kim SH Kim KH Hur GC Joo Yim H Chung HK Ho Woo S Dong Koo K Lee CS Sung Koh J Kim GT 《Bioorganic & medicinal chemistry letters》2007,17(4):937-941
Oxime ethers of alpha-acyl-beta-phenylpropanoic acids were prepared to apply as PPARalpha and gamma dual agonists. Among them, compound 11l proved to exhibit potent in vitro activities with EC(50) of 19 and 13nM in PPARalpha and gamma, respectively. It showed better glucose lowering effects than rosiglitazone 1 and ameliorated the lipid profile like plasma triglyceride in db/db mice model. 相似文献
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Mogensen JP Jeppesen L Bury PS Pettersson I Fleckner J Nehlin J Frederiksen KS Albrektsen T Din N Mortensen SB Svensson LA Wassermann K Wulff EM Ynddal L Sauerberg P 《Bioorganic & medicinal chemistry letters》2003,13(2):257-260
Using a known dual PPARalpha/gamma activator (5) as a structural template, SAR evaluations led to the identification of triple PPARalpha/gamma/delta activators (18-20) with equal potency and efficacy on all three receptors. These compounds could become useful tools for studying the combined biological effects of PPARalpha/gamma/delta activation. 相似文献
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A series of azaindole-alpha-alkyloxyphenylpropionic acid analogues was synthesized and evaluated for PPAR agonist activities. Structure-activity relationship was developed for PPARalpha/gamma dual agonism. One of the synthesized compound 7a was identified as a potent, selective PPARalpha/gamma dual agonist. 相似文献
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Kim E Park CS Han T Bae MH Chong W Lee CH Shin YA Ahn BN Kim MK Shin CY Son MH Kim JK Moon HS Shim HJ Kim EJ Kim SH Lim JI Lee CH 《Bioorganic & medicinal chemistry letters》2008,18(18):4993-4996
Aryl-tetrahydropyridine derivatives were prepared and their PPARalpha/gamma dual agonistic activities were evaluated. Among them, compound (S)-5b was identified as a potent PPARalpha/gamma dual agonist with an EC(50) of 1.73 and 0.64 microM in hPPARalpha and gamma, respectively. In diabetic (db/db) mice, compound (S)-5b showed good glucose lowering efficacy and favorable pharmacokinetic properties. 相似文献
10.
Kumar R Ramachandran U Khanna S Bharatam PV Raichur S Chakrabarti R 《Bioorganic & medicinal chemistry》2007,15(3):1547-1555
A novel series of l-tyrosine derivatives have been reported with potential PPARalpha/gamma dual agonistic activity. In vitro cell based PPARalpha/gamma transactivation studies have shown compound 4a and compound 4f to be the most potent PPARgamma and PPARalpha activators, respectively. Molecular docking studies performed on these series of compounds have complemented the experimental results and have led to interesting inferences. 相似文献
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Fibrate and statin synergistically increase the transcriptional activities of PPARalpha/RXRalpha and decrease the transactivation of NFkappaB. 总被引:3,自引:0,他引:3
Ikuo Inoue Fumiaki Itoh Shigemi Aoyagi Shigeki Tazawa Hiroshi Kusama Masuo Akahane Toshiyuki Mastunaga Kenji Hayashi Takuya Awata Tugikazu Komoda Sigehiro Katayama 《Biochemical and biophysical research communications》2002,290(1):131-139
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Seethala R Golla R Ma Z Zhang H O'Malley K Lippy J Cheng L Mookhtiar K Farrelly D Zhang L Hariharan N Cheng PT 《Analytical biochemistry》2007,363(2):263-274
Peroxisome proliferator-activated receptors (PPARs) and other members of the nuclear hormone receptor family are important drug targets for the treatment of metabolic diseases. PPARalpha and PPARgamma play crucial roles in lipid and glucose metabolism, respectively. Therefore, screening methods that help to rapidly identify activators of these receptors should be of considerable value. A homogeneous fluorescence polarization (FP) ligand binding assay capable of rapidly identifying ligands that bind to both PPARalpha and PPARgamma has been developed using purified PPARalpha or PPARgamma ligand binding domains and a fluorescein-labeled analog (FLA) of a potent dual PPARalpha/gamma activator. FLA activator showed good binding affinity toward both PPARalpha (K(i)=0.7microM) and PPARgamma (K(i)=0.4microM). The binding of FLA activator was rapid and reached a plateau within 10 min. The resulting FP signal was stable for at least 18h. The FP binding assay performed robustly in a 384-well format, and the average Z' value was 0.77. There was a good correlation between the binding potency (IC(50) values) and rank order of binding potency for a panel of standard PPAR ligands obtained in FP binding assay and scintillation proximity assay or gel filtration binding assays using (3)H-labeled PPARalpha (r(2)=0.99) and PPARgamma (r(2)=0.99) ligands. There was also a good correlation of IC(50) values obtained by FP binding assay and scintillation proximity assay for the clinically used PPAR activators. Thus, the FP binding assay with a single fluorescein-labeled PPARalpha/gamma dual activator offers a homogeneous nonradioactive, sensitive, robust, and less expensive high-throughput assay for detecting compounds that bind to both PPARgamma and PPARalpha. Using this FP binding assay, we have identified a large number of PPARalpha/gamma dual activators. A similar assay platform may be easily adapted to other members of the nuclear hormone receptor family. 相似文献
15.
Humphries PS Almaden JV Barnum SJ Carlson TJ Do QQ Fraser JD Hess M Kim YH Ogilvie KM Sun S 《Bioorganic & medicinal chemistry letters》2006,16(23):6116-6119
A series of novel pyridine-2-propanoic acids was synthesized. A structure-activity relationship study of these compounds led to the identification of potent dual PPARalpha/gamma agonists with varied isoform selectivity. Based on the results of efficacy studies in diabetic (db/db) mice, and the desired pharmacokinetic parameters, compound (S)-13 was selected for further profiling. 相似文献
16.
Devasthale PV Chen S Jeon Y Qu F Ryono DE Wang W Zhang H Cheng L Farrelly D Golla R Grover G Ma Z Moore L Seethala R Sun W Doweyko AM Chandrasena G Sleph P Hariharan N Cheng PT 《Bioorganic & medicinal chemistry letters》2007,17(8):2312-2316
A novel series of potent dual agonists of PPARalpha and PPARgamma, the alkoxybenzylglycines, was identified and explored using a solution-phase library approach. The synthesis and structure-activity relationships of this series of dual PPARalpha/gamma agonists are described. 相似文献
17.
Pingali H Jain M Shah S Makadia P Zaware P Goel A Patel M Giri S Patel H Patel P 《Bioorganic & medicinal chemistry》2008,16(15):7117-7127
A few novel 1,3-dioxane carboxylic acid derivatives were designed and synthesized to aid in the characterization of PPAR alpha/gamma dual agonists. Structural requirements for PPARalpha/gamma dual agonism of 1,3-dioxane carboxylic acid derivatives included the structural similarity with potent glitazones in fibric acid chemotype. The compounds with this pharmacophore and substituted oxazole as a lipophilic heterocyclic tail were synthesized and evaluated for their in vitro PPAR agonistic potential and in vivo hypoglycemic and hypolipidemic efficacy in animal models. Lead compound 2-methyl-c-5-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-ylmethoxy)-benzyl]-1,3-dioxane-r-2-carboxylic acid 13b exhibited potent hypoglycemic, hypolipidemic and insulin sensitizing effects in db/db mice and Zucker fa/fa rats. 相似文献
18.
Sharma S Sowjanya A Kumari M Suryaprakash R Cynthia G Suresh J Chakrabarti R 《Life sciences》2006,80(3):235-244
The current goal in the treatment of diabetes is not only to enhance the glycemic control but also to improve the associated cardiovascular risk factors. Among many of the strategies available, a co-ligand of PPARalpha and gamma in a single molecule which combines the insulin sensitizing potential of PPARgamma and the beneficial lipid modulating properties of PPARalpha agonism, has gained attention in the recent past. Here we report the biochemical mechanism by which a dual PPAR alpha/gamma agonist Ragaglitazar (Raga) achieves this goal. The PPARalpha component of Raga appears to contribute to a significant increase in beta oxidation, ApoA1 secretion and inhibition of TG biosynthesis in HepG2 cells. These effects of Raga at 60 microM were similar to that shown by Fenofibrate (Feno) at 250 microM. The PPARgamma component of Raga showed significant G3PDH activity and TG accumulation with a corresponding increase in aP2 expression in 3T3L1 cells. Significantly reduced levels of IL-6 and TNFalpha were observed in the culture supernatants of Raga treated 3T3L1 cells. Raga resulted in significant insulin dependent glucose uptake in 3T3L1 with a corresponding increase in GLUT4 expression. Further, Raga showed a significant cholesterol efflux with a corresponding increase in ABCA1 protein expression in THP-1 macrophages. In conclusion, Raga activates both PPARalpha and gamma regulated pathway in adipocytes as well as in hepatocytes which together contributes for its insulin sensitizing and lipid lowering activity. In addition the dual activation of PPAR alpha/gamma also shows an athero-protective potential by inducing reverse cholesterol efflux and inhibiting the pro-inflammatory cytokines. 相似文献
19.
Impaired skin wound healing in peroxisome proliferator-activated receptor (PPAR)alpha and PPARbeta mutant mice 总被引:13,自引:0,他引:13
Michalik L Desvergne B Tan NS Basu-Modak S Escher P Rieusset J Peters JM Kaya G Gonzalez FJ Zakany J Metzger D Chambon P Duboule D Wahli W 《The Journal of cell biology》2001,154(4):799-814
We show here that the alpha, beta, and gamma isotypes of peroxisome proliferator-activated receptor (PPAR) are expressed in the mouse epidermis during fetal development and that they disappear progressively from the interfollicular epithelium after birth. Interestingly, PPARalpha and beta expression is reactivated in the adult epidermis after various stimuli, resulting in keratinocyte proliferation and differentiation such as tetradecanoylphorbol acetate topical application, hair plucking, or skin wound healing. Using PPARalpha, beta, and gamma mutant mice, we demonstrate that PPARalpha and beta are important for the rapid epithelialization of a skin wound and that each of them plays a specific role in this process. PPARalpha is mainly involved in the early inflammation phase of the healing, whereas PPARbeta is implicated in the control of keratinocyte proliferation. In addition and very interestingly, PPARbeta mutant primary keratinocytes show impaired adhesion and migration properties. Thus, the findings presented here reveal unpredicted roles for PPARalpha and beta in adult mouse epidermal repair. 相似文献
20.
A series of 2-alkoxydihydrocinnamates were synthesized as PPARgamma and PPARalpha dual agonists. In vitro studies in cell model showed that these compounds were efficacious. Compound 1g was found to be a potent PPARalpha/gamma dual agonist and will be further evaluated for the treatment of type II diabetes. 相似文献