Structure-based drug design of a novel family of chalcones as PPARα agonists: Virtual screening, synthesis, and biological activities in vitro

Acta Pharmacologica Sinica

Volumn 28, Issue 12, 2007, Pages 2040-2052

  Li, Xiang Hua ^a   Zou, Han Jun ^a   Wu, An Hui ^a   Ye, Yang Liang ^a   Shen, Jian Hua ^a  

^a SHANGHAI INSTITUTE OF MATERIA MEDICA   (China)

Author keywords

Drug design; Peroxisome proliferator activated receptors; Virtual screening

Indexed keywords

2 [4 (2 HYDROXYETHYL)PHENOXY] 2 METHYLPROPIONIC ACID ETHYL ESTER; 2 [4 [2 (4 FORMYLPHENOXY)ETHYL]PHENOXY] 2 METHYLPROPIONIC ACID ETHYL ESTER; 2 [4 [2 [3 HYDROXY 4 (3 PHENYLACRYLOYL)PHENOXY]ETHYL]PHENOXY] 2 METHYLPROPIONIC ACID; 2 [4 [2 [4 [3 (2 HYDROXY 5 METHOXYPHENYL) 3 OXOPROPENYL]PHENOXY]ETHYL]PHENOXY] 2 METHYLPROPIONIC ACID; 2 [4 [2 [4 [3 (2 HYDROXY 5 METHYLPHENYL) 3 OXOPROPENYL]PHENOXY]ETHYL]PHENOXY] 2 METHYLPROPIONIC ACID; 2 [4 [2 [4 [3 (2 HYDROXYPHENYL) 3 OXO PROPENYL]PHENOXY]ETHYL]PHENOXY] 2 METHYLPROPIONIC ACID; 2 [4 [2 [4 [3 (5 CHLORO 2 HYDROXYPHENYL) 3 OXOPROPENYL]PHENOXY]ETHYL]PHENOXY] 2 METHYLPROPIONIC ACID; 2 [4 [2 [4 HYDROXY 3 (3 PHENYLACRYLOYL)PHENOXY]ETHYL]PHENOXY] 2 METHYLPROPIONIC ACID; 2 METHYL 2 [4 [2 (4 OXO 2 PHENYLCHROMAN 6 YLOXY)ETHYL]PHENOXY]PROPIONIC ACID ETHYL ESTER; 2 METHYL 2 [4 [2 (4 OXO 2 PHENYLCHROMAN 7 YLOXY)ETHYL]PHENOXY]PROPIONIC ACID ETHYL ESTER; BEZAFIBRATE; CHALCONE DERIVATIVE; CLOFIBRATE; DE 001; DE 002; DE 003; DE 004; DE 005; DE 006; DE 007; DE 008; DE 009; DE 010; DE 011; DE 012; DE 013; DE 014; DE 015; DE 016; DE 017; DE 018; DE 019; DE 021; DE 022; DE 023; DE 024; DE 025; DE 026; DE 027; DE 028; DE 029; DE 030; DE 031; DE 032; DE 033; DE 034; DE 035; DE 036; DE 037; FENOFIBRATE; MICRONOMICIN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR AGONIST; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ARTICLE; BIOASSAY; BIOLOGICAL ACTIVITY; CONCENTRATION RESPONSE; DRUG SCREENING; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; HUMAN CELL; STRUCTURE ANALYSIS;

CHALCONES; DRUG DESIGN; MAGNETIC RESONANCE SPECTROSCOPY; MODELS, MOLECULAR; PPAR ALPHA; SPECTROMETRY, MASS, ELECTROSPRAY IONIZATION;

EID: 36649022448     PISSN: 16714083     EISSN: 17457254     Source Type: Journal    
DOI: 10.1111/j.1745-7254.2007.00670.x     Document Type: Article

References (32)

1. Anum EA, Adera T. Hypercholesterolemia and coronary heart disease in the elderly: a meta-analysis. Ann Epidemiol 2004 14:705 21.
2. Auboeuf D, Rieusset J, Fajas L, Vallier P, Frering V, Riou JP, et al. Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-alpha in humans: no alteration in adipose tissue of obese and NIDDM patients. Diabetes 1997 46:1319 27.
3. Banner CD, Gottlicher M, Widmark E, Sjovall J, Rafter JJ, Gustafsson JA. A systematic analytical chemistry/cell assay approach to isolate activators of orphan nuclear receptors from biological extracts: characterization of peroxisome proliferator-activated receptor activators in plasma. J Lipid Res 1993 34:1583 91.
4. Chong PH, Bachenheimer BS. Current, new and future treatments in dyslipidaemia and atherosclerosis. Drugs 2000 60:55 93.
5. Brown PJ, Winegar DA, Plunket KD, Moore LB, Lewis MC, Wilson JG, et al. A ureido-thioisobutyric acid (GW9578) is a subtype-selective PPARalpha agonist with potent lipid-lowering activity. J Med Chem 1999 42:3785 8.
6. Bunnelle WH, Dart MJ, Schrimpf MR. Design of ligands for the nicotinic acetylcholine receptors: the quest for selectivity. Curr Top Med Chem 2004 4:299 334.
7. Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC. Mechanism of action of fibrates on lipid and lipo-protein metabolism. Circulation 1998 98:2088 93.
8. El-Jack AK, Hamm JK, Pilch PF, Farmer SR. Reconstitution of insulin-sensitive glucose transport in fibroblasts requires expression of both PPARgamma and C/EBPalpha. J Biol Chem 1999 274:7946 51.
9. Willson TM, Brown PJ, Sternbach DD, Henke BR. The PPARs: from orphan receptors to drug discovery. J Med Chem 2000 43:527 50.
10. Hertz R, Bishara-Shieban J, Bar-Tana J. Mode of action of per-oxisome proliferators as hypolipidemic drugs. Suppression of apolipoprotein C-III. J Biol Chem 1995 270:13 470 5.
11. Kliewer SA, Umesono K, Noonan DJ, Heyman RA, Evans RM. Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature 1992 358:771 4.
12. Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem 1995 270:12 953 6.
13. Berthou L, Duverger N, Emmanuel F, Langouet S, Auwerx J, Guillouzo A, et al. Opposite regulation of human versus mouse apolipoprotein A-I by fibrates in human apolipoprotein A-I transgenic mice. J Clin Invest 1996 97:2408 16.
14. Li Z, Liao C, Ko BC, Shan S, Tong EH, Yin Z, et al. Design, synthesis, and evaluation of a new class of noncyclic 1,3-dicarbonyl compounds as PPARalpha selective activators. Bioorg Med Chem Lett 2004 14:3507 11.
15. Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, et al. The nuclear receptor superfamily: the second decade. Cell 1995 83:835 9.
16. Nolte RT, Wisely GB, Westin S, Cobb JE, Lambert MH, Kurokawa R, et al. Ligand binding and co-activator assembly of the peroxisome proliferator- activated receptor-gamma. Nature 1998 395:137 43.
17. Delerive P, De Bosscher K, Besnard S, Vanden Berghe W, Peters JM, Gonzalez FJ, et al. Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1. J Biol Chem 1999 274:32 048 54.
18. Forman BM, Chen J, Evans RM. Hypolipidemic drugs, polyun-saturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci USA 1997 94:4312 7.
19. Pinelli A, Godio C, Laghezza A, Mitro N, Fracchiolla G, Tortorella V, et al. Synthesis, biological evaluation, and molecular modeling investigation of new chiral fibrates with PPARalpha and PPARgamma agonist activity. J Med Chem 2005 48:5509 19.
20. Wahli W, Braissant O, Desvergne B. Peroxisome proliferator activated receptors: transcriptional regulators of adipogenesis, lipid metabolism and more. Chem Biol 1995 2:261 6.
21. Wang JL, Liu D, Zhang ZJ, Shan S, Han X, Srinivasula SM, et al. Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells. Proc Natl Acad Sci USA 2000 97:7124 9.
22. Ni LM, Meng CQ, Sikorski JA. Recent advances in therapeutic chalcones. Exp Opin Ther Patents 2004 14:1669 91.
23. Sierra ML, Beneton V, Boullay AB, Boyer T, Brewster AG, Donche F, et al. Substituted 2-[(4-aminomethyl)phenoxy]-2-methylpro-pionic acid PPARalpha agonists. 1. Discovery of a novel series of potent HDLc raising agents. J Med Chem 2007 50:685 95.
24. Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, et al. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 1998 19:1639 62.
25. Tanaka N, Tamai T, Mukaiyama H, Hirabayashi A, Muranaka H, Ishikawa T, et al. Beta(3)-adrenoceptor agonists for the treatment of frequent urination and urinary incontinence: 2-[4-(2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1- methylethyl] amino]ethyl) phenoxy]-2-methylpropionic acid. Bioorg Med Chem 2001 9:3265 71.
26. Ahn C, Correia R, DeShong P. Mechanistic study of the Mitsunobu reaction. J Org Chem 2002 67:1751 3.
27. Daskiewicz JB, Depeint F, Viornery L, Bayet C, Comte-Sarrazin G, Comte G, et al. Effects of flavonoids on cell proliferation and caspase activation in a human colonic cell line HT29: an SAR study. J Med Chem 2005 48:2790 804.
28. Park H, Lee J, Lee S. Critical assessment of the automated AutoDock as a new docking tool for virtual screening. Proteins 2006 65:549 54.
29. Marcus SL, Miyata KS, Rachubinski RA, Capone JP. Transactivation by PPAR/RXR heterodimers in yeast is potentiated by exogenous fatty acid via a pathway requiring intact peroxisomes. Gene Expr 1995 4:227 39.
30. Henke BR, Blanchard SG, Brackeen MF, Brown KK, Cobb JE, Collins JL, et al. N-(2-Benzoylphenyl)-L-tyrosine PPARγ agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents. J Med Chem 1998 41:5020 36.
31. Zheng SX, Luo XM, Chen G, Zhu WL, Shen JH, Chen KX, et al. A new rapid and effective chemistry space filter in recognizing a druglike database. J Chem Inf Model 2005 45:856 62.
32. Chen G. Structure-based combinatorial focus library design: Methodologies and applications PhD Thesis Shanghai:Shanghai Institute of Materia Medica 2003.