Azaxanthene based selective glucocorticoid receptor modulators: Design, synthesis, and pharmacological evaluation of (S)-4-(5-(1-((1,3,4-Thiadiazol-2- yl)amino)-2-methyl-1-oxopropan-2-yl)-5 H-chromeno[2,3-b]pyridin-2-yl)-2-fluoro- N, N-dimethylbenzamide (BMS-776532) and its methylene homologue (BMS-791826)

Journal of Medicinal Chemistry

Volumn 54, Issue 20, 2011, Pages 7318-7333

  Weinstein, David S ^a   Gong, Hua ^a   Doweyko, Arthur M ^a   Cunningham, Mark ^a   Habte, Sium ^a   Wang, Jin Hong ^a   Holloway, Deborah A ^a   Burke, Christine ^a   Gao, Ling ^a   Guarino, Victor ^a   Carman, Julie ^a   Somerville, John E ^a   Shuster, David ^a   Salter Cid, Luisa ^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 [4 [(ETHYLMETHYLAMINO)CARBONYL] 3 FLUOROPHENYL] ALPHA,ALPHA DIMETHYL N 1,3,4 THIADIAZOL 2 YL 5H BENZOPYRANO[2,3 B]PYRIDIN 5 ACETAMIDE; 4 [5 [1 [(1,3,4 THIADIAZOL 2 YL)AMINO] 2 METHYL 1 OXOPROPAN 2 YL] 5H CHROMENO[2,3 B]PYRIDIN 2 YL] 2 FLUORO N,N DIMETHYLBENZAMIDE; ALKALINE PHOSPHATASE; ANTIINFLAMMATORY AGENT; BMS 776532; BMS 791826; CELL NUCLEUS RECEPTOR; DEXAMETHASONE; GLUCOCORTICOID RECEPTOR; GLUTAMATE AMMONIA LIGASE; HORMONE RECEPTOR AFFECTING AGENT; INTERLEUKIN 1BETA; INTERLEUKIN 8; LIPOPOLYSACCHARIDE; PARTIAL AGONIST; PREDNISOLONE; TRANSCRIPTION FACTOR; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG; XANTHENE DERIVATIVE;

ADJUVANT ARTHRITIS; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIINFLAMMATORY ACTIVITY; AREA UNDER THE CURVE; ARTICLE; BINDING AFFINITY; CELL ASSAY; CHRONIC INFLAMMATION; CONTROLLED STUDY; CYTOKINE PRODUCTION; DOSE RESPONSE; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG DESIGN; DRUG EFFICACY; DRUG ELIMINATION; DRUG HALF LIFE; DRUG PENETRATION; DRUG RECEPTOR BINDING; DRUG SCREENING; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; HALOGENATION; HUMAN; INFLAMMATION; MALE; MAXIMUM PLASMA CONCENTRATION; NONHUMAN; PAW EDEMA; RAT; STRUCTURAL HOMOLOGY; TIME TO MAXIMUM PLASMA CONCENTRATION; TRANSACTIVATION;

ALKALINE PHOSPHATASE; ANIMALS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; ARTHRITIS, EXPERIMENTAL; CELL LINE, TUMOR; DRUG PARTIAL AGONISM; EDEMA; GLUTAMATE-AMMONIA LIGASE; HETEROCYCLIC COMPOUNDS, 3-RING; HUMANS; INTERLEUKIN-1BETA; MALE; MODELS, MOLECULAR; RATS; RATS, INBRED LEW; RATS, SPRAGUE-DAWLEY; RECEPTORS, GLUCOCORTICOID; RESPONSE ELEMENTS; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; THIADIAZOLES; TRANSCRIPTION FACTOR AP-1; TRANSCRIPTIONAL ACTIVATION; TUMOR NECROSIS FACTOR-ALPHA; TYROSINE TRANSAMINASE;

EID: 80054936721     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm200879j     Document Type: Article

References (36)

1. Cheng, Y. and Prusoff, W. H. Biochem. Pharmacol. 1973, 22, 3099 - 3108
2. Webster, N. J. G., Green, S., Jin, J. R., and Chambon, P. Cell 1988, 54 (2), 199 - 207
3. Goulding, N. J. and Flower, R. J., Ed. Glucocorticoids; Birkhäuser Verlag: Basel, Switzerland, 2001.
4. Buttgereit, F.; Burmester, G.-R.; Lipworth, B. J. Optimised glucocorticoid therapy: the sharpening of an old spear Lancet 2005, 365, 801-806
5. Berlin, M. Recent advances in the development of novel glucocorticoid receptor modulators Expert Opin. Ther. Pat. 2010, 20, 855-873
6. 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 (Pubitemid 351982564)
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 (Pubitemid 351982593)
8. Schäcke, H.; Berger, M.; Hansson, T. G.; McKerrecher, D.; Rehwinkel, H. Expert Opin. Ther. Pat. 2008, 18, 339
9. Regan, 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. For a very recent disclosure, see the following
10. Riether, D.; Harcken, C.; Razavi, H.; Kuzmich, D.; Gilmore, T.; Bentzien, J.; Pack, E. J., Jr.; 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
11. Newton, R.; Holden, N. S. Separating transrepression and transactivation: a distressing divorce for the glucocorticoid receptor? Mol. Pharmacol. 2007, 72, 799-809 (Pubitemid 47481403)
12. Clark, A. R. Anti-inflammatory functions of glucocorticoid-induced genes Mol. Cell. Endocrinol. 2007, 275, 79-97 (Pubitemid 47259278)
13. Beck, I. M. E.; Berghe, W. V.; Vermeulen, L.; Yamamoto, K. R.; Haegeman, G.; De Bosscher, K. Crosstalk in inflammation: the interplay of glucocorticoid receptor-based mechanisms and kinases and phosphatases Endocr. Rev. 2009, 30, 830-882
14. 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
15. Yang, B. V.; Weinstein, D. S.; Doweyko, L. M.; Gong, H.; Vaccaro, W.; Huynh, T.; Xiao, H.; Doweyko, A. M.; McKay, L.; Holloway, D. A.; Somerville, J. E.; Habte, S.; Cunningham, M.; McMahon, M.; Townsend, R.; Shuster, D.; Dodd, J. H.; Nadler, S. G.; Barrish, J. C. Dimethyl-diphenyl-propanamide derivatives as nonsteroidal dissociated glucocorticoid receptor agonists J. Med. Chem. 2010, 53, 8241-8251
16. Wang, Y.; Zhong, D.; Chen, X.; Zheng, J. Identification of quinone methide metabolites of dauricine in human liver microsomes and rat bile Chem. Res. Toxicol. 2009, 22, 824-834
17. Monks, T. J.; Jones, D. C. The metabolism and toxicity of quinines, quinonimines, quinine methods, and quinine-thioethers Curr. Drug Metab. 2002, 3, 425-438 (Pubitemid 34778005)
18. Bledsoe, R. K.; Montana, V. G.; Stanley, T. B.; Thomas, 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 (Pubitemid 34874609)
19. Suino-Powell, K.; Xu, Y.; Zhang, C.; Tao, Y.-G.; Tolbert, W. D.; Simons, S. S.; Xu, H. E. Doubling the size of the glucocorticoid receptor ligand binding pocket by deacylcortivazol Mol. Cell. Biol. 2008, 28, 1915-1923 (Pubitemid 351342623)
20. Biggadike, K.; Bledsoe, R. K.; Coe, D. M.; Cooper, T. W. J.; House, D.; Iannone, M. A.; Macdonald, S. J. F.; Madauss, K. P.; McLay, I. M.; Shipley, T. J.; Taylor, S. J.; Tran, T. B.; Uings, I. J.; Weller, V.; Williams, S. P. Design and X-ray crystal structures of high-potency nonsteroidal glucocorticoid agonists exploiting a novel binding site on the receptor Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 18114-18119
21. Doweyko, A. M. Steroid nuclear hormone receptors: the allosteric conversation Drug Dev. Res. 2007, 68, 95-106 (Pubitemid 47502821)
22. Paliogianni, F.; Boumpas, D. T. In Glucocorticoids; Goulding, N. J.; Flower, R. J., Eds.; Birkhauser Verlag: Basel, Switzerland, 2001; pp 81-101.
23. Rhen, T.; Cidlowski, J. A. Antiinflammatory action of glucocorticoids-new mechanisms for old drugs N. Engl. J. Med. 2005, 353, 1711-1723
24. Brattsand, R.; Linden, M. Cytokine modulation by glucocorticoids: mechanisms and actions in cellular studies Aliment. Pharmacol. Ther. 1996, 10 (Suppl. 2) 81-90 (Pubitemid 26341300)
25. Sabokbar, A.; Millett, P. J.; Myer, B.; Rushton, N. A rapid, quantitative assay for measuring alkaline phsophatase activity in osteoblastic cells in vitro Bone Miner. 1994, 27, 57-67
26. Santoro, J. C.; Harris, G.; Sitlani, A. Colorimetric detection of glutamine synthetase-catalyzed transferase activity in glucocorticoid-treated skeletal muscle cells Anal. Biochem. 2001, 289, 18-25 (Pubitemid 32121564)
27. Minet, R.; Villie, F.; Marcollet, M.; Meynial-Denis, D.; Cynober, L. Measurement of glutamine synthetase activity in rat muscle by a colorimetric assay Clin. Chim. Acta 1997, 268, 121-132 (Pubitemid 28066807)
28. Schäcke, H.; Döcke, W.-D.; Asadullah, K. Mechanisms involved in the side effects of glucocorticoids Pharmacol. Ther. 2002, 23-43 (Pubitemid 35346616)
29. Nicolaides, N. C.; Galata, Z.; Kino, T.; Chrousos, G. P.; Charmandari, E. The human glucocorticoid receptor: molecular basis of biologic function Steroids 2010, 75, 1-12
30. Haller, J.; Mikics, E.; Makara, G. B. The effects of non-genomic glucocorticoid mechanisms on bodily functions and the central nervous system. A critical review of findings Front. Neuroendocrinol. 2008, 29, 273-291 (Pubitemid 351467120)
31. Newton, R.; Leigh, R.; Giembycz, M. A. Pharmacological strategies for improving the efficacy and therapeutic ratio of glucocorticoids in inflammatory lung diseases Pharmacol. Ther. 2010, 125, 283-327
32. Goulding, N. J. The molecular complexity of glucocorticoid actions in inflammation-a four-ring circus Curr. Opin. Pharmacol. 2004, 4, 629-666
33. Chrousos, G. P.; Kino, T. Intracellular glucocorticoid signaling: a formerly simple system turns stochastic Sci. STKE 2005, 304, pe48
34. Wang, J. C.; Shah, N.; Pantoja, C.; Meijsing, S. H.; Ho, J. D.; Scanlan, T. S.; Yamamoto, K. R. Novel arylpyrazole compounds selectively modulate glucocorticoid receptor regulatory activity Genes Dev. 2006, 20, 689-699
35. Granner, D. K.; Tomkins, G. M. Methods Enzymol. 1970, 633 - 637
36. Diamondstone, T. I. Anal. Biochem. 1966, 16, 395 - 401