Discovery of isoindoline and tetrahydroisoquinoline derivatives as potent, selective PPARδ agonists

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 1, 2011, Pages 492-496

  Luckhurst, Christopher A ^a   Stein, Linda A ^a   Furber, Mark ^a   Webb, Nicola ^a   Ratcliffe, Marianne J ^a   Allenby, Gary ^a   Botterell, Sara ^a   Tomlinson, Wendy ^a   Martin, Barrie ^a   Walding, Andrew ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

Isoindolines; PPAR agonism; Tetrahydroisoquinolines

Indexed keywords

[2 METHYL 4 [4 METHYL 2 (4 TRIFLUOROMETHYLPHENYL) 5 THIAZOLYLMETHYLTHIO]PHENOXY]ACETIC ACID; ISOINDOLINE DERIVATIVE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA AGONIST; PYRUVATE DEHYDROGENASE KINASE 4; TETRAHYDROISOQUINOLINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; DOSE RESPONSE; DRUG BINDING; DRUG EFFICACY; DRUG IDENTIFICATION; DRUG METABOLISM; DRUG SYNTHESIS; FATTY ACID OXIDATION; HUMAN; HUMAN CELL; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION; UPREGULATION;

BINDING SITES; CATALYTIC DOMAIN; COMPUTER SIMULATION; HUMANS; INDOLES; PPAR DELTA; PROTEIN-SERINE-THREONINE KINASES; STRUCTURE-ACTIVITY RELATIONSHIP; TETRAHYDROISOQUINOLINES;

EID: 78650517125     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.10.117     Document Type: Article

References (28)

1. P. Linsel-Nitscke, and A.R. Tall Nat. Rev. Drug Disc. 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. S. Weigand, H. Bischoff, E. Dittrich-Wengenroth, H. Heckroth, D. Lang, A. Vaupel, and M. Woltering Bioorg. Med. Chem. Lett. 15 2005 4619
7. 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
8. Bischoff, H.; Dittrich-Wengenroth, E.; Heckroth, H.; Vaupel, A.; Woltering, M.; Weigand, S. WO2003035603; Chem. Abstr. 2003, 138, 353734.
9. Urbahns, K.; Woltering, M.; Nikolic, S.; Pernerstorfer, J.; Hinzen, B.; Dittrich-Wengenroth, E.; Bischoff, H.; Hirth-Dietrich, C.; Lustig, K. WO2002028821; Chem. Abstr. 2002, 136, 294653.
10. I. Pettersson, S. Ebdrup, M. Havranek, P. Pihera, M. Korinek, J.P. Mogensen, C.B. Jeppesen, E. Johansson, and P. Sauerberg Bioorg. Med. Chem. Lett. 17 2007 4625
11. M. Havranek, P. Sauerberg, J.P. Mogensen, P. Kratina, C.B. Jeppesen, I. Pettersson, and P. Pihera Bioorg. Med. Chem. Lett. 17 2007 4144
12. Kuo, G.-H.; Zhang, Y.; Shen, L.; Lu, S.; Demarest, K. T.; Peiton, P. US2007244094; Chem. Abstr. 2007, 147, 469249.
13. R. Epple, R. Russo, M. Azimioara, C. Cow, Y. Xie, X. Wang, J. Wityak, D. Karanewsky, A. Gerken, M. Iskandar, E. Saez, H.M. Seidel, and S. Tian Bioorg. Med. Chem. Lett. 16 2006 4376
14. R. Epple, M. Azimioara, R. Russo, Y. Xie, X. Wang, C. Cow, J. Wityak, D. Karanewsky, B. Bursulaya, A. Kreusch, T. Tuntland, A. Gerken, M. Iskandar, E. Saez, H.M. Seidel, and S. Tian Bioorg. Med. Chem. Lett. 16 2006 5488
15. Epple, R.; Russo, R.; Azimioara, M.; Xie, Y. WO2005113519; Chem. Abstr. 2005, 144, 22911.
16. R. Epple, M. Azimioara, R. Russo, B. Bursulaya, S. Tian, A. Gerken, and M. Iskandar Bioorg. Med. Chem. Lett. 16 2006 2969
17. Deangelis, A.; Demarest, K. T.; Kuo, G.-H.; Pelton, P.; Wang, A.; Zhang, R. US2006058393; Chem. Abstr. 2006, 144, 311792.
18. R. Zhang, A. Wang, A. Deangelis, P. Pelton, J. Xu, P. Zhu, L. Zhou, K.T. Demarest, W.V. Murray, and G.-H. Kuo Bioorg. Med. Chem. Lett. 17 2007 3855
19. J. Kasuga, T. Oyama, I. Nakagome, M. Makishima, S. Hirono, K. Morikawa, Y. Hashimoto, and H. Miyachi ChemMedChem 3 2008 1662
20. J. Kasuga, I. Nakagome, A. Aoyama, K. Sako, M. Ishizawa, M. Ogura, M. Makishima, S. Hirono, Y. Hashimoto, and H. Miyachi Bioorg. Med. Chem. 15 2007 5177
21. Keil, S.; Wendler, W.; Glien, M.; Goerlitzer, J.; Chandross, K.; Mcgarry, D. G.; Merrill, J.; Bernardelli, P.; Ronan, B.; Terrier, C. WO2005097786; Chem. Abstr. 2008, 148, 472054.
22. H. Fujieda, S. Usui, T. Suzuki, H. Nakagawa, M. Ogura, M. Makishima, and N. Miyata Bioorg. Med. Chem. Lett. 17 2007 4351
23. R. Zhang, A. DeAngelis, A. Wang, E. Sieber-McMaster, X. Li, R. Russell, P. Pelton, J. Xu, P. Zhu, L. Zhou, K. Demarest, W.V. Murray, and G. Kuo Bioorg. Med. Chem. 19 2009 1101
24. c log P 4.3 is a predicted octanol/water partition coefficient from Daylight Chemical Information Systems and BioByte Corp.
25. HEK293 cells are stably transfected with a construct comprising the ligand-binding domain of human PPARδ fused to the GAL4 DNA binding domain. It has been confirmed that the primary PPARδ screening assay contains the most common sequence of PPARD (NM-006238 ). The cell also stably expresses a luciferase gene under the control of a GAL4 promoter. Hence, compounds which bind and activate the PPARδ/GAL4 fusion promote luciferase production, which is quantified by measuring luminescence generated from a luciferase substrate. GW501516, 1, was used as reference compound in every assay to ensure assay stability, and the intrinsic activity of this compound is set to 100%, against which all project compounds are scaled.
26. T. Ooi, E. Tayama, M. Yamada, and K. Maruoka Synlett 6 1999 729
27. + = 499, 501.
28. Human skeletal muscle myoblast cells were isolated by enzymatic digestion from the vastus lateralis. The myoblasts were differentiated for 7 days in 2% horse serum. Cells were treated with compound for 24 h before measuring fold induction of PDK4 mRNA.