Minor structural modifications convert a selective PPARα agonist into a potent, highly selective PPARδ agonist

Bioorganic and Medicinal Chemistry Letters

Volumn 15, Issue 20, 2005, Pages 4619-4623

  Weigand, Stefan ^a   Bischoff, Hilmar ^a   Dittrich Wengenroth, Elke ^a   Heckroth, Heike ^a   Lang, Dieter ^a   Vaupel, Andrea ^a,b   Woltering, Michael ^a  

^a BAYER PHARMA AG   (Germany)

^b NOVARTIS PHARMA AG   (Switzerland)

Author keywords

PPAR delta agonists

Indexed keywords

PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR DELTA AGONIST; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; CHEMICAL MODIFICATION; CHEMICAL STRUCTURE; DRUG BLOOD LEVEL; DRUG POTENCY; DRUG POTENTIATION; DRUG SELECTIVITY; DRUG STRUCTURE; HUMAN; HUMAN CELL; NONHUMAN; PROTON NUCLEAR MAGNETIC RESONANCE; RAT; SOLID PHASE SYNTHESIS;

PPAR ALPHA; PPAR DELTA; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 24344474876     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.06.023     Document Type: Article

References (17)

1. P. Linsel-Nitscke, and A.R. Tall Nature Rev. Drug Discov. 4 2005 193
2. T.M. Willson, P.J. Brown, D.D. Sternbach, and B.R. Henke J. Med. Chem. 43 2000 527
3. T.M. Willson, and W. Wahli Curr. Opin. Chem. Biol. 1 1997 235
4. M.L. Sznaidman, C.D. Haffner, P.R. Maloney, A. Fivush, E. Chao, D. Goreham, M.L. Sierra, C. LeGrumelec, H.E. Xu, V.G. Montana, M.H. Lambert, T.M. Willson, W.R. Oliver Jr., and D.D. Sternbach Bioorg. Med. Chem. Lett. 13 2003 1517
5. W.R. Oliver Jr., J.L. Shenk, M.R. Snaith, C.S. Russell, K.D. Plunket, N.L. Bodkin, M.C. Lewis, D.A. Winegar, M.L. Sznaidman, M.H. Lambert, H.E. Xu, D.D. Sternbach, S.A. Kliewer, B.C. Hansen, and T.M. Willson Proc. Natl. Acad. Sci. U.S.A. 98 2001 5306
6. A.D. Adams, W. Yuen, Z. Hu, C. Santini, A.B. Jones, K.L. MacNaul, J.P. Berger, T.W. Doebber, and D.E. Moller Bioorg. Med. Chem. Lett. 13 2003 931
7. Bischoff, H.; Dittrich-Wengenroth, E.; Heckroth, H.; Vaupel, A.; Woltering, M.; Weigand, S. (Bayer Health Care AG), WO 03/035603 2003; Chem. Abstr. 2003, 138, 353734.
8. Urbahns, K.; Woltering, M.; Nikolic, S.; Pernerstorfer, J.; Hinzen, B.; Dittrich-Wengenroth, E.; Bischoff, H.; Hirth-Dietrich, C.; Lustig, K. (Bayer Health Care AG), WO 02/028821 2002; Chem. Abstr. 2002, 136, 294653.
9. K.C. Nicolaou, X.-P. Xiao, Z. Parandoosh, A. Senyei, and M.P. Nova Angew. Chem. 107 1995 2476
10. Angew. Chem. Int. Ed. Eng. 34 1995 2289
11. 3): δ = 1.10-1.40 (m, 3H), 1.55 (m, 2H), 1.70 (m, 1H), 1.93 (m, 2H), 2.14 (m, 2H), 2.16 (s, 3H), 3.41 (m, 1H), 4.09 (s, 2H), 4.21 (s, 2H), 4.62 (s, 2H), 6.57 (d, J = 8.3 Hz, 1H), 7.03 (dd, J = 1.9 and 8.2 Hz, 1H), 7.10 (d, J = 1.8 Hz, 1H), 7.17 (dd, J = 2.3 and 8.7 Hz, 1H), 7.31 (d, J = 2.3 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 9.57 (s, 1H).
12. K.G. Liu, M.H. Lambert, L.M. Leesnitzer, W. Oliver Jr., R.J. Ott, K.D. Plunket, L.W. Stuart, P.J. Brown, T.M. Willson, and D.D. Sternbach Bioorg. Med. Chem. Lett. 11 2001 2959
13. 7,8
14. The results are based on two to three independent experiments each dose done in triplicate (SD = 20%).
15. All compounds (except 29) are full agonists on PPARδ with >70% efficacy, e.g. 33: PPARδ 2 nM, 75% efficacy; PPARα /γ >10 μM, 30% efficacy.
16. T.M. Willson, P.J. Brown, D.D. Sternbach, and B.R. Henke J. Med. Chem. 43 2004 527
17. H.E. Xu, M.H. Lambert, V.G. Montana, D.J. Parks, S.G. Blanchard, P.J. Brown, D.D. Sternbach, J.M. Lehman, G.B. Wisely, T.M. Willson, S.A. Kliewer, and M.V. Milburn Mol. Cell 3 1999 397