Substituted indanylacetic acids as PPAR-α-γ activators

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 2, 2006, Pages 297-301

  Lowe, Derek B ^a   Bifulco, Neil ^a   Bullock, William H ^a   Claus, Thomas ^a   Coish, Philip ^a   Dai, Miao ^a   Dela Cruz, Fernando E ^a   Dickson, David ^a   Fan, Dongping ^a   Hoover Litty, Helana ^a   Li, Tindy ^a   Ma, Xin ^a   Mannelly, Gretchen ^a   Monahan, Mary Katherine ^a   Muegge, Ingo ^a   O'Connor, Stephen ^a   Rodriguez, Mareli ^a   Shelekhin, Tatiana ^a   Stolle, Andreas ^a   Sweet, Laurel ^a   Wang, Ming ^a   Wang, Yamin ^a   Zhang, Chengzhi ^a   Zhang, Hai Jun ^a   Zhang, Mingbao ^a   Zhao, Kake ^a   Zhao, Qian ^a   Zhu, Jian ^a   Zhu, Lei ^a   Tsutsumi, Manami ^a   more..

^a BAYER CORPORATION   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACETIC ACID DERIVATIVE; CELL NUCLEUS RECEPTOR; OXAZOLE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; RECEPTOR SUBTYPE; ROSIGLITAZONE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; DYSLIPIDEMIA; MOUSE; NONHUMAN;

ACETIC ACIDS; ADMINISTRATION, ORAL; ANIMALS; BLOOD GLUCOSE; CHOLESTEROL, HDL; DRUG EVALUATION, PRECLINICAL; LIGANDS; MICE; MICE, MUTANT STRAINS; MICE, OBESE; MOLECULAR STRUCTURE; OXAZOLES; PPAR ALPHA; PPAR GAMMA; STRUCTURE-ACTIVITY RELATIONSHIP; TRIGLYCERIDES;

ANIMALIA;

EID: 27944459156     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.10.008     Document Type: Article

References (24)

1. Overviews: V.J. Ram Drugs Today 39 2003 609
2. D.D. Sternbach Ann. Rep. Med. Chem. 38 2003 71
3. A.R. Miller, and G.J. Etgen Expert Opin. Invest. Drugs 12 2003 1489
4. T.M. Willson, P.J. Brown, D.D. Sternbach, and B.R. Henke J. Med. Chem. 43 2000 527
5. PPAR-α: D.H. van Raalte, M. Li, P.H. Pritchard, and K.M. Wasan Pharm. Res. 21 2004 1531
6. H. Miyachi Expert Opin. Ther. Pat. 14 2004 607
7. PPAR-γ: B.R. Henke Prog. Med. Chem. 42 2004 1
8. L. Fajas, and J. Auwerx Handbook of Obesity 2nd ed 2004 Marcel Dekker New York 559
9. R.M. Evans, G.D. Barish, and Y.-X. Wang Nat. Med. 10 2004 355
10. H.A. Pershadsingh Expert Opin. Invest. Drugs 13 2004 215
11. PPAR-δ: N.S. Tan, L. Michalik, B. Desvergne, and W. Wahli Expert Opin. Ther. Targets 8 2004 39
12. Review: B. Henke J. Med. Chem. 47 2004 4118
13. J.L. Collins, S.G. Blanchard, E. Boswell, P.S. Charifson, J.E. Cobb, B.R. Henke, E.A. Hull-Ryde, W.M. Kazmierski, D.H. Lake, L.M. Leesnitzer, J. Lehmann, J.M. Lenhard, L.A. Orband-Miller, Y. Gray-Nunez, D.J. Parks, K.D. Plunkett, and W.-Q. Tong J. Med. Chem. 41 1995 5037
14. M. Zhang, L. Zhu, X. Ma, M. Dai, and D. Lowe Org. Lett. 5 2003 1587
15. A.G. Godfrey, D.A. Brooks, L.A. Hay, M. Peters, J.R. McCarthy, and D. Mitchell J. Org. Chem. 68 2003 2623
16. 1H NMR and LC/MS data. For more details on their synthetic preparations, see: Lowe, D. B.; Wickens, P. L.; Ma, X.; Zhang, M.; Bullock, W. H.; Coish, P. D. G.; Muegge, I. A.; Stolle, A.; Wang, M.; Wang, Y.; Zhang, C.; Zhang, H.-J.; Zhu, L.; Tsutsumi, M.; Livingston, J. N. U.S. Patent 6,828,335, 2004.
17. Test compounds were incubated in 96-well plates with europium-labeled anti-GST antibody, GST-tagged PPAR ligand-binding domain, biotinylated CREB-binding protein, and streptavidin-labeled APC (Wallac, AD0065). The plate was read in a fluorimeter with an excitation wavelength of 340 nm and emission wavelengths of 615 and 640 nm.
18. 50 values were determined based on a dose-response and the percent maximum stimulation was assessed by comparison to reference compounds.
19. 5-Trifluoromethyl compounds: M. Kawase, H. Miyamae, and T. Kurihara Chem. Pharm. Bull. 46 1998 749
20. Oxadiazole preparation adapted from: G.A. Showell, T.L. Gibbons, C.O. Kneen, A.M. MacLeod, K. Merchant, J. Saunders, S.B. Freedman, S. Patel, and R. Baker J. Med. Chem. 34 1991 1086
21. G.R. Madhavan, R. Chakrabarti, S.K. Kumar, P. Misra, R.N. Mamidi, V. Balraju, K. Kasiram, R.K. Babu, J. Suresh, B.B. Lohray, V.B. Lohrayb, J. Iqbal, and R. Rajagopalan Eur. J. Med. Chem. 36 2001 627
22. The intermediate for compound 26 was prepared according to: M.S. Malamas, R.P. Carlson, D. Grimes, R. Howell, K. Glaser, I. Gunawan, J.A. Nelson, M. Kanzelberger, U. Shah, and D.A. Hartman J. Med. Chem. 39 1996 237
23. Male db/db mice (n = 8/group) were provided with ad lib access to water and chow. Test compound or vehicle (0.5% methylcellulose) was administered by oral gavage once daily for 14 days. After the final dose, the animals were euthanized and blood was collected and analyzed for glucose levels.
24. Male hApoA1 mice (n = 16/group) were provided with ad lib access to water and chow. Test compound or vehicle (0.5% methylcellulose) was administered by oral gavage once daily for eight days. After the final dose, animal were euthanized, and serum was prepared from the collected blood and analyzed for triglyceride content.