Discovery of a novel class of 2-mercaptohexanoic acid derivatives as highly active PPARα agonists

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 15, 2009, Pages 4421-4426

  Zettl, Heiko ^a   Steri, Ramona ^a   Lämmerhofer, Michael ^b   Schubert Zsilavecz, Manfred ^a  

^a GOETHE UNIVERSITY   (Germany)

^b UNIVERSITY OF VIENNA   (Austria)

Author keywords

2 Mercaptohexanoic acid; PPAR; PPAR agonists; SAR

Indexed keywords

1,3 PROPANEDIOL; 2 MERCAPTOHEXANOIC ACID DERIVATIVE; BENZENE; CARBON; HEXANOIC ACID DERIVATIVE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PYRIMIDINE; SULFUR; UNCLASSIFIED DRUG;

ARTICLE; DRUG STRUCTURE; DRUG SYNTHESIS; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION; TRANSACTIVATION;

CARBON; CHEMISTRY, ORGANIC; CHEMISTRY, PHARMACEUTICAL; COMBINATORIAL CHEMISTRY TECHNIQUES; DRUG DESIGN; DRUG EVALUATION, PRECLINICAL; HEXANOIC ACIDS; HUMANS; MODELS, CHEMICAL; MOLECULAR STRUCTURE; PHENOL; PPAR ALPHA; STRUCTURE-ACTIVITY RELATIONSHIP; SULFHYDRYL COMPOUNDS; SULFUR;

EID: 67649965623     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.05.057     Document Type: Article

References (18)

1. Rau O., Zettl H., Popescu L., Steinhilber D., and Schubert-Zsilavecz M. ChemMedChem 3 (2008) 206
2. Keech A., Simes R., Barter P., Best J., Scott R., Taskinen M., Forder P., Pillai A., Davis T., Glasziou P., Drury P., Kesaniemi Y., Sullivan D., Hunt D., Colman P., d'Emden M., Whiting M., Ehnholm C., and Laakso M. Lancet 366 (2005) 1849
3. Circulation 102 (2000) 21
4. Staels B., Maes M., and Zambon A. Nat. Clin. Pract. Cardiovasc. Med. 5 (2008) 542
5. Asaki T., Aoki T., Hamamoto T., Sugiyama Y., Ohmachi S., Kuwabara K., Murakami K., and Todo M. Bioorg. Med. Chem. 16 (2008) 981
6. Kuhn B., Hilpert H., Benz J., Binggeli A., Grether U., Humm R., Marki H., Meyer M., and Mohr P. Bioorg. Med. Chem. Lett. 16 (2006) 4016
7. Feldman P.L., Lambert M.H., and Henke B.R. Curr. Top. Med. Chem. 8 (2008) 728
8. Rau O., Syha Y., Zettl H., Kock M., Bock A., and Schubert-Zsilavecz M. Arch. Pharm. (Weinheim) 341 (2008) 191
9. Aranapakam V., Grosu G.T., Davis J.M., Hu B., Ellingboe J., Baker J.L., Skotnicki J.S., Zask A., DiJoseph J.F., Sung A., Sharr M.A., Killar L.M., Walter T., Jin G., and Cowling R. J. Med. Chem. 46 (2003) 2361
10. Humphries P.S., Almaden J.V., Barnum S.J., Carlson T.J., Do Q.Q., Fraser J.D., Hess M., Kim Y.H., Ogilvie K.M., and Sun S. Bioorg. Med. Chem. Lett. 16 (2006) 6116
11. Humphries P.S., Do Q.Q., and Wilhite D.M. Beilstein J. Org. Chem. 2 (2006) 21
12. Bargiggia F., and Piva O. Tetrahedron: Asymmetry 14 (2003) 1819
13. Usui S., Fujieda H., Suzuki T., Yoshida N., Nakagawa H., Ogura M., Makishima M., and Miyata N. Chem. Pharm. Bull. (Tokyo) 55 (2007) 1053
14. 2. The day before transfection, cells were seeded in 96-well plates in a density of 30,000 cells/well. Transfection was carried out by Lipofectamine™ 2000 reagent (Invitrogen) according to the manufacturer's protocol with pFR-Luc (Stratagene), pRL-SV40 (Promega) and the Gal4-fusion receptor plasmids (pFA-CMV-hPPAR-LBD) of the respective subtype. 5 h after transfection, medium was changed to DMEM without FCS, containing 0.1% DMSO and the respective concentrations of the test compounds.Following overnight incubation with the test compounds, cells were assayed for reportergene activity using Dual-Glo™ Luciferase Assay System (Promega) according to the manufacturer's protocol. Luminescence was measured with a GENios Pro luminometer (Tecan).Each concentration of the compounds was tested in triplicate wells and each experiment was repeated independently at least three times.
15. Zettl H., Dittrich M., Steri R., Proschak E., Rau O., Steinhilber D., Schneider G., Lämmerhofer M., and Schubert-Zsilavecz M. QSAR Combinatorial Sci. 28 (2009) 576
16. Pinelli A., Godio C., Laghezza A., Mitro N., Fracchiolla G., Tortorella V., Lavecchia A., Novellino E., Fruchart J.C., Staels B., Crestani M., and Loiodice F. J. Med. Chem. 48 (2005) 5509
17. Mandl A., Nicoletti L., Lammerhofer M., and Lindner W. J. Chromatogr., A 858 (1999) 1
18. Lämmerhofer, M.; Pell, R.; Richter, M.; Schiesel, S.; Mahut, M.; Zettl, H.; Dittrich, M.; Schubert-Zsilavecz, M.; Lindner, W. Chirality, in preparation.