Synthesis and evaluation of aminomethyl dihydrocinnamates as a new class of PPAR ligands

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 24, 2006, Pages 6328-6333

  Warshawsky, Alan M ^a   Alt, Charles A ^a   Brozinick, Joseph T ^a   Harkness, Allen R ^a   Hawkins, Eric D ^a   Henry, James R ^a   Matthews, Donald P ^a   Miller, Anne R ^a   Misener, Elizabeth A ^a   Montrose Rafizadeh, Chahrzad ^a   Rhodes, Gary A ^a   Shen, Quanrong ^a   Vance, Jennifer A ^a   Udodong, Uko E ^a   Wang, Minmin ^a   Zhang, Tony Y ^a   Zink, Richard W ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

PPAR

Indexed keywords

AMINOMETHYL DIHYDROCINNAMATE DERIVATAIVE; CINNAMIC ACID DERIVATIVE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; ROSIGLITAZONE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; DOSE RESPONSE; DRUG EFFECT; DRUG RECEPTOR BINDING; DRUG SCREENING; DRUG SYNTHESIS; GLUCOSE BLOOD LEVEL; IC 50; MALE; MOUSE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; RAT; TREATMENT OUTCOME; TRIACYLGLYCEROL BLOOD LEVEL;

CINNAMATES; HUMANS; HYPOGLYCEMIC AGENTS; LIGANDS; PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS; PPAR ALPHA; PPAR GAMMA; STRUCTURE-ACTIVITY RELATIONSHIP; THIAZOLIDINEDIONES;

RODENTIA;

EID: 33750736061     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.09.011     Document Type: Article

References (24)

1. PPAR reviews:. Staels B., and Fruchart J.-C. Diabetes 54 (2005) 2460
2. Etgen G.J., and Mantlo N. Curr. Top. Med. Chem. 3 (2003) 1649
3. Miller A.R., and Etgen G.J. Expert Opin. Investig. Drugs 12 (2003) 1489
4. Willson T.M., Brown P.J., Sternbach D.D., and Henke B.R. J. Med. Chem. 43 (2000) 527
5. Parks D.J., Tomkinson N.C.O., Villeneuve M.S., Blanchard S.G., and Willson T.M. Bioorg. Med. Chem. Lett. 8 (1998) 3657
6. Gampe R.T., Montana V.G., Lambert M.H., Miller A.B., Bledsoe R.K., Milburn M.V., Kliewer S.A., Willson T.M., and Xu H.E. Mol. Cell 5 (2000) 545
7. Nolte R.T., Wisely G.B., Westin S., Cobb J.T., Lambert M.H., Kurokawa R., Rosenfeld M.G., Willson T.M., Glass C.K., and Milburn M.V. Nature 395 (1998) 137
8. Haigh D., Allen G., Birrell H.C., Buckle D.R., Cantello B.C.C., Eggleston D.S., Haltiwanger R.C., Holder J.C., Lister C.A., Pinto I.L., Rami H.K., Sime J.T., Smith S.A., and Sweeney J.D. Bioorg. Med. Chem. 7 (1999) 821
9. Henke B.R., Blanchard S.G., Brackeen M.F., Brown K.K., Cobb J.E., Collins J.L., Harrington Jr. W.W., Hashim M.A., Hull-Ryde E.A., Kaldor I., Kliewer S.A., Lake D.H., Leesnitzer L.M., Lehmann J., Lenhard J.M., Orband-Miller L.A., Miller J.F., Mook R.A., Noble S.A., Oliver W., Parks D.J., Plunket K.D., Szewczyk J.R., and Willson T.M. J. Med. Chem. 41 (1998) 5020
10. Collins J.L., Blanchard S.G., Boswell G.E., Charifson P.S., Cobb J.E., Henke B.R., Hull-Ryde E.A., Kazmierski W.M., Lake D.H., Leesnitzer L.M., Lehmann J., Lenhard J.M., Orband-Miller L.A., Gray-Nunez Y., Parks D.J., Plunket K.D., and Tong W.-Q. J. Med. Chem. 41 (1998) 5036
11. Cobb J.E., Blanchard S.G., Boswell G.E., Brown K.K., Cooper J.P., Collins J.L., Dezube M., Henke B.R., Hull-Ryde E.A., Lake D.H., Leesnitzer L.M., Lenhard J.M., Oliver Jr. W., Oplinger J., Pentti M., Parks D.J., Plunket K.D., and Tong W.-Q. J. Med. Chem. 41 (1998) 5055
12. Sorbera L.A., Leeson P.A., Martin L., and Castaner J. Drugs Future 26 (2001) 354
13. Harrity T., Farrelly D., Tieman A., Chu C., Kunselman L., Gu L., Ponticiello R., Cap M., Qu F., Shao C., Wang W., Zhang H., Fenderson R., Chen S., Devasthale P., Jeon Y., Seethala R., Yang W.-P., Ren J., Zhou M., Biller S., Mookhtiar K.A., Wetterau J., Gregg R., Cheng P.T., and Hariharan N. Diabetes 55 (2006) 240
14. McIntyre J.A., and Castaner J. Drugs Future 29 (2004) 1084
15. Martin J.A., Brooks D.A., Prieto L., Gonzalez R., Torrado A., Rojo I., Lopez de Uralde B., Lamas C., Ferritto R., Dolores Martin-Ortega M., Agejas J., Parra F., Rizzo J.R., Rhodes G.A., Robey R.L., Alt C.A., Wendel S.R., Zhang T.Y., Reifel-Miller A., Montrose-Rafizadeh C., Brozinick J.T., Hawkins E., Misener E.A., Briere D.A., Ardecky R., Fraser J.D., and Warshawsky A.M. Bioorg. Med. Chem. Lett. 15 (2005) 51
16. Shinkai H., Onogi S., Tanaka M., Shibata T., Iwao M., Wakitani K., and Uchida I. J. Med. Chem. 41 (1998) 1927 preparation of mesylate
17. Brooks D.A., Etgen G.J., Rito C.J., Shuker A.J., Dominianni S.J., Warshawsky A.M., Ardecky R., Paterniti J.R., Tyhonas J., Karanewsky D.S., Kauffman R.F., Broderick C.L., Oldham B.A., Montrose-Rafizadeh C., Winneroski L.L., Faul M.M., and McCarthy J.R. J. Med. Chem. 44 (2001) 2061
18. Compounds were docked into the PPAR LBDs using CDocker:. Vieth M., Hirst J.D., Kolinski A., and Brooks III C.L. J. Comput. Chem. 19 (1998) 1612
19. Vieth M., Hirst J.D., Dominy B.N., Daigler H., and Brooks III C.L. J. Comput. Chem. 19 (1998) 1623
20. db/db mouse studies. Five-week-old db/db mice were purchased from Jackson Laboratories (Bar Harbor, ME, USA). After a 2-week acclimation period, the mice were pre-bled and assigned to three groups (vehicle, rosiglitazone, and test compound; 5 animals per group) based on starting plasma glucose and body weight (day -1).
21. Zucker diabetic fatty (ZDF) rat studies. Male ZDF rats were obtained from Charles River (Genetic Models, Inc, Indianapolis, IN, USA) at 6 weeks of age. After a 2-week acclimation period, rats were pre-bled and assigned to four groups (5 animals per group; vehicle, test compound at the stated dose, or rosiglitazone at 10.0 mg/kg/day) based on starting plasma glucose levels and body weight (day -1). In both animal models, compounds were administered daily by oral gavage between 8:30 and 9:30 AM for 7 days. The dosing vehicle was 1% w/v CMC, 0.25% Tween 80. Blood samples were obtained 1 hour post-dose on day 7; following centrifugation of blood samples, plasma was used for measurements of glucose and triglyceride levels. Statistical significance was determined by one-way ANOVA. When statistical significance was detected with this method, group differences were determined by Neuman-Keuls post hoc analyses.
22. Wang M., Winneroski L.L., Ardecky R.J., Babine R.E., Brooks D.A., Etgen G.J., Hutchison D.R., Kauffman R.F., Kunkel A., Mais D.E., Montrose-Rafizadeh C., Ogilvie K.M., Oldham B.A., Peters M.K., Rito C.J., Rungta D.K., Tripp A.E., Wilson S.B., Xu Y., Zink R.W., and McCarthy J.R. Bioorg. Med. Chem. Lett. 14 (2004) 6113
23. Keller H., Devchnad P.R., Perroud M., and Wahli W. Biol. Chem. 378 (1997) 651
24. Mukherjee R., Jow L., Noonan D., and McDonnell D.P. J. Steroid Biochem. Mol. Biol. 51 (1994) 157