Nonsteroidal 2,3-dihydroquinoline glucocorticoid receptor agonists with reduced PEPCK activation

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 6, 2011, Pages 1654-1657

  Hudson, Andrew R ^a   Higuchi, Robert I ^a   Roach, Steven L ^a   Valdez, Lino J ^a   Adams, Mark E ^a   Vassar, Angie ^a   Rungta, Deepa ^a   Syka, Peter M ^a   Mais, Dale E ^a   Marschke, Keith B ^a   Zhi, Lin ^a  

^a LIGAND PHARMACEUTICALS INC   (United States)

Author keywords

Anti inflammatory; Glucocorticoid; Oxime; Quinoline; SEGRA; SGRM

Indexed keywords

2,3 DIHYDROQUINOLINE DERIVATIVE; 3 CHLOROINDOLE DERIVATIVE; 4 QUINOLONE DERIVATIVE; 6 ARYL 1,2,3,4 TETRAHYDROQUINOLINE DERIVATIVE; ANTIINFLAMMATORY AGENT; DEXAMETHASONE; GLUCOCORTICOID RECEPTOR; GLUCOCORTICOID RECEPTOR AGONIST; HORMONE RECEPTOR STIMULATING AGENT; PHOSPHOENOLPYRUVATE CARBOXYKINASE (GTP); PREDNISOLONE; UNCLASSIFIED DRUG;

ANTIINFLAMMATORY ACTIVITY; ARTICLE; CONCENTRATION RESPONSE; DRUG EFFICACY; DRUG MECHANISM; DRUG MEGADOSE; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG STRUCTURE; ENZYME ACTIVATION; GLUCONEOGENESIS; HUMAN; IC 50; INFLAMMATION; LUPUS VULGARIS; NONHUMAN; RHEUMATOID ARTHRITIS; STRUCTURE ACTIVITY RELATION; TRANSACTIVATION;

CARBOXY-LYASES; ENZYME ACTIVATION; QUINOLINES; RECEPTORS, GLUCOCORTICOID; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 79952363835     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2011.01.104     Document Type: Article

References (23)

1. For recent reviews see: K. De Bosscher, and G. Haegeman Mol. Endocrinol. 23 2010 281
2. H. Schacke, M. Berger, T.G. Hansson, D. McKerrecher, and H. Rehwinkel Exp. Opin. Ther. Pat. 18 2008 339
3. A.R. Hudson, S.L. Roach, and R.I. Higuchi Curr. Top. Med. Chem. 8 2008 750
4. H. Takahashi, H. Razavi, and D. Thomson Curr. Top. Med. Chem. 8 2008 521
5. S.L. Roach, R.I. Higuchi, M.E. Adams, Y. Liu, D.S. Karanewsky, K.B. Marschke, D.E. Mais, J.N. Miner, and L. Zhi Bioorg. Med. Chem. Lett. 18 2008 3504
6. S.L. Roach, R.I. Higuchi, A.R. Hudson, M.E. Adams, P.M. Syka, D.E. Mais, J.N. Miner, K.B. Marschke, and L. Zhi Bioorg. Med. Chem. Lett. 21 2011 168
7. A.R. Hudson, R.I. Higuchi, S.L. Roach, M.E. Adams, A. Vassar, P.M. Syka, D.E. Mais, J.N. Miner, K.B. Marschke, and L. Zhi Bioorg. Med. Chem. Lett. 21 2011 1697
8. A.R. Hudson, S.L. Roach, R.I. Higuchi, D.P. Phillips, R.P. Bissonette, W.W. Lamph, J. Yen, Y. Li, M.E. Adams, L.J. Valdez, C. Cuervo, E.A. Kallel, C.J. Gharbaoui, D.E. Mais, J.N. Miner, K.B. Marschke, D. Rungta, A. Negro-Vilar, and L. Zhi J. Med. Chem. 50 2007 4699
9. R.J. Ardecky, A.R. Hudson, D.P. Phillips, J.S. Tyhonas, C. Deckhut, T.L. Lau, Y. Li, E.A. Martinborough, S.L. Roach, R.I. Higuchi, F.J. Lopez, K.B. Marschke, J.N. Miner, D.S. Karanewsky, A. Negro-Vilar, and L. Zhi Bioorg. Med. Chem. Lett. 17 2007 4158
10. P.R. Kym, M.E. Kort, M.J. Coghlan, J.L. Moore, R. Tang, J.D. Ratajczyk, D.P. Larson, S.W. Elmore, J.K. Pratt, M.A. Stashko, H.D. Falls, C.W. Lin, M. Nakane, L. Miller, C.M. Tyree, J.N. Miner, P.B. Jacobson, D.M. Wilcox, P. Nguyen, and B.C. Lane J. Med. Chem. 46 2003 1016
11. S.W. Elmore, J.K. Pratt, M.J. Coghlan, Y. Mao, B.E. Green, D.D. Anderson, M.A. Stashko, C.W. Lin, D. Falls, M. Nakane, L. Miller, C.M. Tyree, J.N. Miner, and B. Lane Bioorg. Med. Chem. Lett. 14 2004 1721
12. A. Schottelius, H. Schäcke, P. Strehlke, W.-D. Döcke, N. Schmees, S. Jaroch, H. Hennekes, H. Rehwinkel, and K. Asadullah Proc. Natl. Acad. Sci. 101 2004 227
13. C.F. Thompson, N. Quraishi, A. Ali, R.T. Mosley, J.R. Tata, M.L. Hammond, J.M. Balkovec, M. Einstein, L. Ge, G. Harris, T.M. Kelly, P. Mazur, S. Pandit, J. Santoro, A. Sitlani, C. Wang, J. Williamson, D.K. Miller, T.T. Yamin, C.M. Thompson, E.A. O'Neill, D. Zaller, M.J. Forrest, E. Carballo-Jane, and S. Luell Bioorg. Med. Chem. Lett. 17 2007 3354
14. N. Shah, and T.S. Scanlan Bioorg. Med. Chem. Lett. 14 2004 5199
15. M. Barker, M. Clackers, R. Copley, D.A. Demaine, D. Humphreys, G.G.A. Inglis, M.J. Johnston, H.T. Jones, M.V. Haase, D. House, R. Loiseau, L. Nisbet, F. Pacquet, P.A. Skone, S.E. Shanahan, D. Tape, V.M. Vinader, M. Washington, I. Uings, R. Upton, I.M. McLay, and S.J.F. MacDonald J. Med. Chem. 49 2006 4216 4231
16. R. Betageri, Y. Zhang, R.M. Zindell, D. Kuzmich, T.M. Kirrane, J. Bentzien, M. Cardozo, A.J. Capolino, T.N. Fadra, R.M. Nelson, Z. Paw, D.-T. Shih, C.-K. Shih, L. Zuvela-Jelaska, G. Nabozny, and D.S. Thomson Bioorg. Med. Chem. Lett. 15 2005 4761
17. J. Regan, T.W. Lee, R.M. Zindell, Y. Bekkali, J. Bentzien, T. Gilmore, A. Hammach, T.M. Kirrane, A.J. Kukulka, D. Kuzmich, R.M. Nelson, J.R. Proudfoot, M. Ralph, J. Pelletier, D. Souza, L. Zuvela-Jelaska, G. Nabozny, and D.S. Thomson J. Med. Chem. 49 2006 7887
18. K. Biggadike, M. Boudjelal, M. Clackers, D.M. Coe, D.A. Demaine, G.W. Hardy, D. Humphreys, G.G.A. Inglis, M.J. Johnston, H.T. Jones, D. House, R. Loiseau, D. Needham, P.A. Skone, I. Uings, G. Veitch, G.G. Weingarten, I.M. McLay, and S.J.F. MacDonald J. Med. Chem. 50 2007 6519
19. H. Takahashi, Y. Bekkali, A.J. Capolino, T. Gilmore, S.E. Goldrick, P.V. Kaplita, L. Liu, R.M. Nelson, D. Terenzio, J. Wang, L. Zuvela-Jelaska, J. Proudfoot, G. Nabozny, and D. Thompson Bioorg. Med. Chem. Lett. 17 2007 5091
20. S.W. Elmore, M.J. Coghlan, D.D. Anderson, J.K. Pratt, B.E. Green, A.X. Wang, M.A. Stashko, C.-W. Lin, C.M. Tyree, J.N. Miner, P.B. Jacobson, D.M. Wilcox, and B.C. Lane J. Med. Chem. 44 2001 4481
21. NMR studies confirmed the regioisomer isolated for representative analog 19 by observing NOE's between H3-H18/H18-H3, and H3-H20/H20-H3 protons.
22. Oxime analogs were isolated as a mixture of oxime regioisomers that were readily separated by preparative HPLC and individually characterized. The corresponding regioisomeric oxime-analogs of compounds 26-28 were found to be devoid of GR-mediated TR activity. Regioisomeric assignment based on analogy with compound 19.
23. E. Imai, P-E. Stromstedt, P.G. Quinn, J. Carlstedt-Duke, J.-A. Gustafsson, and D.K. Granner Mol. Cell. Biol. 10 1990 4172