Dimethyl-diphenyl-propanamide derivatives as nonsteroidal dissociated glucocorticoid receptor agonists

Journal of Medicinal Chemistry

Volumn 53, Issue 23, 2010, Pages 8241-8251

  Yang, Bingwei V ^a   Weinstein, David S ^a   Doweyko, Lidia M ^a   Gong, Hua ^a   Vaccaro, Wayne ^a   Huynh, Tram ^a   Xiao, Hai Yun ^a   Doweyko, Arthur M ^a   McKay, Lorraine ^a   Holloway, Deborah A ^a   Somerville, John E ^a   Habte, Sium ^a   Cunningham, Mark ^a   McMahon, Michele ^a   Townsend, Robert ^a   Shuster, David ^a   Dodd, John H ^a   Nadler, Steven G ^a   Barrish, Joel C ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 (3 HYDROXY 9H XANTHEN 9 YL) 2 METHYL N (1,3,4 THIADIAZOL 2 YL)PROPANAMIDE; 3 (3 FLUORO 4 HYDROXYPHENYL) 2,2 DIMETHYL 3 PHENYL N (THIAZOL 2 YL)PROPANAMIDE; ANTIINFLAMMATORY AGENT; CARRAGEENAN; GLUCOCORTICOID RECEPTOR; GLUCOSE; PREDNISOLONE; TYROSINE AMINOTRANSFERASE; UNCLASSIFIED DRUG;

AMINOTRANSFERASE BLOOD LEVEL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIINFLAMMATORY ACTIVITY; ARTICLE; CONTROLLED STUDY; DRUG ACTIVITY; DRUG STRUCTURE; GLUCOSE BLOOD LEVEL; HUMAN; HUMAN CELL; MALE; NONHUMAN; PAW EDEMA; PROTEIN EXPRESSION; RAT;

AMIDES; ANIMALS; MODELS, MOLECULAR; RATS; RECEPTORS, GLUCOCORTICOID;

EID: 78649813000     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm100957a     Document Type: Article

References (44)

1. Buttgereit, F.; Burmester, G.-R.; Lipworth, B. J. Optimised glucocorticoid therapy: the sharpening of an old spear Lancet 2005, 365, 801-803
2. Goulding, N. J. The molecular complexity of glucocorticoid actions in inflammation-a four-ring circus Curr. Opin. Pharmacol. 2004, 4, 629-666
3. Reichard, H. M.; Tuckermann, J. P.; Gottlicher, M.; Vujic, M.; Weih, F.; Angel, P.; Herrlich, P.; Schutz, G. Repression of inflammatory responses in the absence of DNA binding by the glucocorticoid receptor EMBO J. 2001, 20, 7168-7173
4. Schacke, H.; Docke, W. D.; Asdullah, K. Mechanisms Involved in the Side Effects of Glucocorticoids Pharmacol. Ther. 2002, 96, 234-243
5. Buckbinder, L.; Robinson, R. P. The Glucocorticoid Receptor: Molecular Mechanism and New Therapeutic Opportunities. Current Drug Targets: Inflammation Allergy 2002, 1, 127-136
6. For recent reviews on the development of dissociated glucocorticoid receptor agonists, see: Hudson, A. R.; Roach, S. L.; Higuchi, R. I. Recent developments in the discovery of selective glucocorticoid receptor modulators (SGRMs) Curr. Top. Med. Chem. 2008, 8, 750-765
7. Takahashi, H.; Razavi, H.; Thomson, D. Recent progress in the discovery of novel glucocorticoid receptor modulators Curr. Top. Med. Chem. 2008, 8, 521-530
8. Schcke, H.; Berger, M.; Hansson, T. G.; McKerrecher, D.; Rehwinkel, H. Dissociated nonsteroidal glucocorticoid receptor modulators: an update on new compounds Expert Opin. Ther. Patents 2008, 18, 339-352
9. Ragan, J.; Razavi, H.; Thomson, D. Advances toward Dissociated Non-steroidal Glucocorticoid Receptor Agonists. In Annual Reports in Medicinal Chemistry; Elsevier: New York, 2008; Vol. 43, Chapter 9, pp 141 - 154
10. Strauss, D. S. Design of small molecules targeting transcriptional activation by NF-kB: overview of recent advances Expert Opin. Drug Discovery 2009, 4, 823-836
11. De Bosscher, K. Selective Glucocorticoid Receptor Modulators J. Steroid Biochem. Mol. Biol. 2010, 120, 96-104
12. Berlin, M. Recent advances in the development of novel glucocorticoid receptor modulators Expert Opin. Ther. Patents 2010, 20, 855-873
13. Abbott/Ligand, selected references: Coghlan, M. J.; Kym, P. R.; Elmore, S. W.; Wang, A. X.; Luly, J. R.; Wilcox, D.; Stashko, M.; Lin, C.-W.; Miner, J.; Tyree, C.; Nakane, M.; Jacobson, P.; Lane, B. C. Synthesis and characterization of nonsteroidal ligands for the glucocorticoid receptor: selective quinoline derivatives with prednisolone-equivalent functional activity J. Med. Chem. 2001, 44, 2879-2885
14. Miner, J. N.; Ardecky, B.; Benbatoul, K.; Griffiths, K.; Larson, C. J.; Mais, D. E.; Marschke, K.; Rosen, J.; Vajda, E.; Zhi, L.; Negro-Vilar, A. Antiinflammatory glucocorticoid receptor ligand with reduced side effects exhibits an altered protein-protein interaction profile Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 19244-19249
15. Schering: Schacke, H.; Schottelius, A.; Docke, W.-D.; Strehlke, P.; Jaroch, S.; Schmees, N.; Rehwinkel, H.; Hennekes, H.; Asadullah, K. Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 227-232
16. Merck: Ali, A.; Thompson, C. F.; Balkovec, J. M.; Graham, D. W.; Hammond, M. L.; Quraishi, N.; Tata, J. R.; Einstein, M.; Ge, L.; Harris, G.; Kelly, T. M.; Mazur, P.; Pandit, S.; Santoro, J.; Sitlani, A.; Wang, C.; Williamson, J.; Miller, D. K.; Thompson, C. M.; Zaller, D. M.; Forrest, M. J.; Carballo-Jane, E.; Luell, S. Novel N -arylpyrazolo[3,2- c ]-based ligands for the glucocorticoid receptor: receptor binding and in vivo activity J. Med. Chem. 2004, 47, 2441-2452
17. Boehringer Ingelheim, selected references: Regan, J; L., T. W.; Zindell, R. M.; Bekkali, Y.; Bentzien, J.; Gilmore, T.; Hammach, A.; Kirrane, T. M.; Kukulka, A. J.; Kuzmich, D.; Nelson, R. M.; Proudfoot, J. R.; Ralph, M.; Pelletie, J.; Souza, D.; Zuvela-Jelaska, L.; Nabozny, G.; Thomson, D. S. Quinol-4-ones as steroid A-ring mimetics in nonsteroidal dissociated glucocorticoid agonists J. Med. Chem. 2006, 49, 7887-7896
18. Kuzmich, D; Kirrane, T.; Proudfoot, J.; Bekkali, Y.; Zindell, R.; Beck, L.; Nelson, R.; Shih, C. K.; Kukulka., A. J.; Paw, Z.; Reilly, P.; Deleon, R.; Cardozo, M.; Nabozny, G.; Thomson, D. Identification of dissociated nonsteroidal glucocorticoid receptor agonists Bioorg. Med. Chem. Lett. 2007, 17, 5025-5031 (Pubitemid 47259678)
19. Riether, D.; Harcken, C.; Razavi, H.; Kuzmich, D.; Gilmore, T.; Bentzien, J.; Pack, E. J.; Souza, D.; Nelson, R. M.; Kukulka, A.; Fadra, T. N.; Zuvela-Jelaska, L.; Pelletier, J.; Dinallo, R.; Panzenbeck, M.; Torcellini, C.; Nabozny, G. H.; Thomson, D. S. Nonsteroidal Dissociated Glucocorticoid Agonists Containing Azaindoles as Steroid A-Ring Mimetics J. Med. Chem. 2010, 53, 6681-6698
20. Mugge, I. A.; Burke, M. J.; Ralph, M. S.; Thomoson, D. S.; Hammach, A.; Kowalski, J. A.; Bentzien, J. M. Glucocorticoid mimetic. Methods of making pharmaceutical compositions, and uses thereof. Patent WO 2006/135826, Dec 21, 2006).
21. Kuzmich, D.; Disalvo, D.; Razavi, H.; Burke, M. J. Methods of making pharmaceutical compositions, and uses thereof. Patent WO 2008/070507, Jun 12, 2008).
22. GlaxoSmithKline, selected references: Biggadike, K.; Boudjelal, M.; Clackers, M.; Coe, D. M.; Demaine, D. A.; Hardy, G. W.; Humphreys, D.; Inglis, G.G. A.; Johnston, M. J.; Jones, H. T.; House, D.; Loiseau, R.; Needham, D.; Skone, P. A.; Uings, I.; Veitch, G.; Weingarten, G. G.; McLay, I. M.; Macdonald, S. J. F. Nonsteroidal glucocorticoid agonists: tetrahydronaphthalenes with alternative steroidal A-ring mimetics possessing dissociated (transrepression/transactivation) efficacy selectivity. J. Med. Chem. 2007, 50, 6519 - 6534, and references herein.
23. Yates, C. M.; Brown, P. J.; Stewart, E. L.; Patten, C.; Austin, R. J. H.; Holt, J. A.; Maglich, J. M.; Angell, D. C.; Sasse, R. Z.; Taylor, S. J.; Uings, I. J.; Trump, R. P. Structure Guided Design of 5-Arylindazole Glucocorticoid Receptor Agonists and Antagonists J. Med. Chem. 2010, 53, 4531-4544
24. Shah, N.; Scanlan, T. S. Design and Evaluation of Novel Glucocorticoid Dissociating Glucocorticoid Receptor Ligands Bioorg. Med. Chem. Lett. 2004, 14, 5199-5203
25. De Bosscher, K.; Vanden Berghe, W.; Beck, I. M.; Van Molle, W.; Hennuyer, N.; Hapgood, J.; Libert, C.; Staels, B.; Louw, A.; Haegeman, G. A Fully Dissociated Compound of Plant Origin for Inflammatory Gene Repression Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 15827-15832
26. Robinson, R. P.; Buckbinder, L.; Haugeto, A. I.; McNiff, P. A.; Millham, M. L.; Reese, M. R.; Schaefer, J. F.; Abramov, Y. A.; Bordner, J.; Chantigny, Y. A.; Kleinman, E. F.; Laird, E. R.; Morgan, B. P.; Murray, J. C.; Salter, E. D.; Wessel, M. D.; Yocum, S. A. Octahydrophenanthrene-2,7-diol Analogues as Dissociated Glucocorticoid Receptor Agonists: Discovery and Lead Exploration J. Med. Chem. 2009, 52, 1731-1743
27. Xiao, H.-Y.; Wu, D.-R.; Malley, M. F.; Gougoutas, J. Z.; Habte, S. F.; Cunningham, M. D.; Somerville, J. E.; Dodd, J. H.; Barrish, J. C.; Nadler, S. G.; Dhar, T. G. M. A Novel Synthesis of the Hexahydroimidazo[1,5 b ]isoquinoline Scaffold: Application to the Synthesis of Glucocorticoid Receptor Modulators J. Med. Chem. 2010, 53, 1270-1280
28. Bai, M.; Carr, G.; Deorazio, R. J.; Friedrich, T. D.; Dobritsa, S.; Fitzpatrick, K.; Guzzo, P. R.; Kitchen, D. B.; Lynch, M. A.; Peace, D.; Sajad, M.; Usyatinsky, A.; Wolf, M. A. 5-Functionalized indazoles as glucocorticoid receptor agonists Bioorg. Med. Chem. Lett. 2010, 20, 3017-3020
29. Yang, B. V.; Vaccaro, W.; Doweyko, A. M.; Doweyko, L. M.; Huynh, T.; Tortolani, D.; Nadler, S. G.; McKay, L.; Somerville, J.; Holloway, D. A.; Habte, S.; Weinstein, D. S.; Barrish, J. C. Discovery of Novel Dihyro-9,10-ethano- anthracene Carboxamides as Glucocorticoid Receptor Modulators Bioorg. Med. Chem. Lett. 2009, 19, 2139-2143
30. Yang, B. V.; Doweyko, L. M.; Vaccaro, W.; Huynh, T.; Doweyko, A. M.; Nadler, S. G.; McKay, L.; Holloway, D. A.; Somerville, J. E.; Habte, S.; Cunningham, M.; Wang, J.; McMahon, M.; Townsend, R.; Shuster, D.; Saltercid, L.; Chen, L.; Tejwani, R.; Dodd, J.; Barrish, J. C. Novel nonsteroidal glucocorticoid receptor modulators: discovery of an agonist trigger in the dimethyl-diphenyl-propanamide series. Presented at the 239th American Chemical Society National Meeting, San Francisco, CA, March 21-25, 2010.
31. Gong, H.; Weinstein, D. S.; Yang, B. V.; Xiao, H.-Y.; Doweyko, A. M.; Chen, P.; Nadler, S. G.; Somerville, J. E.; McKay, L.; Cunningham, M.; Wang, J.; Holloway, D.; Habte, S.; Chen, L.; Dodd, J. H.; Barrish, J. C. Discovery of xanthene-based dissociated agonists of the glucocorticoid receptor. Presented at the 239th American Chemical Society National Meeting, San Francisco, CA, March 21-25, 2010.
32. Burkett, R.; Moresch, G. W. Synthesis of beta-hydroxy acids using alpha-lithiated carboxylic acid salts J. Org. Chem. 1971, 36, 1149-1154
33. Orfanopoulos, M; Smounou, I. Selective reduction of diaryl or aryl alkyl alcohols in the presence of primary hydroxyl or ester group by etherated boron trifluoride-triethylsilane system Synth. Commun. 1988, 18, 833-839
34. Nakabayashi, H.; Taketa, T.; Miyano, K.; Yamane, T.; Sato, J. Growth of human hepatoma cell lines with differentiated functions in chemically defined medium Cancer Res. 1982, 42, 3858-3863
35. Bledsoe, R. K.; Montana, V. G.; Stanley, T. B.; Delves, C. J.; Apolito, C. J.; McKee, D. D.; Consler, T. G.; Parks, D. J.; Stewart, E. L.; Willson, T. M.; Lambert, M. H.; Moore, J. T.; Pearce, K. H.; Xu, H. E. Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition Cell 2002, 110, 93-105
36. A crystal structure of the enantiopure acid 9a, the precursor of 13, was obtained which allowed the assignment of its absolute stereochemistry, therefore defined the S -configuration of compound 13.
37. Dalvie, D. K.; Kalgutkar, A. S.; Khojasteh-Bakht, S. C.; Obach, R. S.; O'Donnell, J. P. Biotransformation Reactions of Five-Membered Aromatic Heterocyclic Rings Chem. Res. Toxicol. 2002, 15, 269-299
38. The absolute stereochemistry of the chromatographically separated enantiomers of 28 was determined by X-ray crystallographic analysis of the (R)(+)- α -methylbenzylamine salt of the R enantiomer (precursor of 31).
39. Baki, L.; Alexis, M. N. Regulation of tyrosine aminotransferase gene expression by glucocorticoids in quiescent and regenerating liver Biochem. J. 1996, 320, 745-753
40. 50) of an enzymatic reaction Biochem. Pharmacol. 1973, 22, 3099-3108
41. Webster, N. J. G.; Green, S.; Jin, J. R.; Chambon, P. The hormone-binding domains of the estrogen and glucocorticoid receptors contain an inducible transcription of a conserved region required for hormonedependent transcriptional activation function Cell 1988, 54, 199-207
42. This assay was developed as a modification of the methods described in the following papers: Granner, D. K.; Tomkins, G. M. Tyrosine Aminotransferase (Rat Liver) Methods Enzymol. 1970, 633-637
43. Diamondstone, T. I. Assay of tyrosine transaminase activity by conversation of p -hydroxyphenylpyruvate to p -hydroxybenzadeheyde Anal. Biochem. 1966, 16, 395-401
44. Reference 9.