Nonsteroidal dissociated glucocorticoid agonists containing azaindoles as steroid A-ring mimetics

Journal of Medicinal Chemistry

Volumn 53, Issue 18, 2010, Pages 6681-6698

  Riether, Doris ^a   Harcken, Christian ^a   Razavi, Hossein ^a   Kuzmich, Daniel ^a   Gilmore, Thomas ^a   Bentzien, Jörg ^a   Pack, Edward J ^a   Souza, Donald ^a   Nelson, Richard M ^a   Kukulka, Alison ^a   Fadra, Tazmeen N ^a   Zuvela Jelaska, Ljiljana ^a   Pelletier, Josephine ^a   Dinallo, Roger ^a   Panzenbeck, Mark ^a   Torcellini, Carol ^a   Nabozny, Gerald H ^a   Thomson, David S ^a  

^a BOEHRINGER INGELHEIM PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1,1,1 TRIFLUORO 4 (2 METHOXY 5 PYRIMIDIN 5 YLPHENYL) 4 METHYL 2 (1H PYRROLO[2,3 C]PYRIDIN 2 YLMETHYL)PENTAN 2 OL; 4 FLUORO 2 [4,4,4 TRIFLUORO 3 HYDROXY 1,1 DIMETHYL 3 (1H PYRROLO[2,3 C]PYRIDIN 2 YLMETHYL)BUTYL]PHENOL; 4 FLUORO 2 [4,4,4 TRIFLUORO 3 HYDROXY 1,1 DIMETHYL 3 (1H PYRROLO[3,2 C]PYRIDIN 2 YLMETHYL)BUTYL]PHENOL; COLLAGEN; DEXAMETHASONE; GLUCOCORTICOID; INDOLE DERIVATIVE; INSULIN; NONSTEROID ANTIINFLAMMATORY AGENT; PREDNISOLONE; UNCLASSIFIED DRUG; 1,1,1-TRIFLUORO-4-(2-METHOXY-5-PYRIMIDIN-5-YLPHENYL)-4-METHYL-2-(1H-PYRROLO(2,3-C)PYRIDIN-2-YLMETHYL)PENTAN-2-OL; 4-FLUORO-2-(4,4,4-TRIFLUORO-3-HYDROXY-1,1-DIMETHYL-3-(1H-PYRROLO(2,3-C)PYRIDIN-2-YLMETHYL)BUTYL)PHENOL; AROMATASE; AROMATASE INHIBITOR; GLUCOCORTICOID RECEPTOR; INTERLEUKIN 1; INTERLEUKIN 6; PYRIDINE DERIVATIVE; PYRROLE DERIVATIVE; STEROID;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIINFLAMMATORY ACTIVITY; ARTHRITIS; ARTICLE; BODY FAT; CHEMICAL REACTION; CONTROLLED STUDY; CYCLIZATION; DRUG SYNTHESIS; GENE REPRESSION; IN VITRO STUDY; INSULIN BLOOD LEVEL; MOUSE; NONHUMAN; RAT; REACTION ANALYSIS; STRUCTURE ACTIVITY RELATION; TRANSACTIVATION; ADIPOSE TISSUE; AGONISTS; ANIMAL; ANTAGONISTS AND INHIBITORS; ARTHRITIS, EXPERIMENTAL; BAGG ALBINO MOUSE; BIOAVAILABILITY; BIOSYNTHESIS; BLOOD; CELL CULTURE; CHEMICAL STRUCTURE; CHEMISTRY; DRUG EFFECTS; ENZYME INDUCTION; FEMALE; GENETICS; HUMAN; HYDROGEN BOND; SPRAGUE DAWLEY RAT; STEREOISOMERISM; SYNTHESIS; TRANSCRIPTION INITIATION;

ADIPOSE TISSUE; ANIMALS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; AROMATASE; AROMATASE INHIBITORS; ARTHRITIS, EXPERIMENTAL; BIOLOGICAL AVAILABILITY; CELLS, CULTURED; ENZYME INDUCTION; FEMALE; HUMANS; HYDROGEN BONDING; INSULIN; INTERLEUKIN-1; INTERLEUKIN-6; MICE; MICE, INBRED BALB C; MODELS, MOLECULAR; PYRIDINES; PYRROLES; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, GLUCOCORTICOID; STEREOISOMERISM; STEROIDS; STRUCTURE-ACTIVITY RELATIONSHIP; TRANSCRIPTIONAL ACTIVATION;

EID: 77956716603     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm100751q     Document Type: Article

References (40)

1. Gupta, R.; Jindal, D. P.; Kumar, G. Corticosteroids: the mainstay in asthma therapy Bioorg. Med. Chem. 2004, 12, 6331-6342
2. Buttgereit, F.; Saag, K. G.; Cutolo, M.; da Silva, J. A. P.; Bijlsma, J. W. J. The molecular basis for the effectiveness, toxicity, and resistance to glucocorticoids: focus on the treatment of rheumatoid arthritis Scand. J. Rheumatol. 2005, 34, 14-21
3. Schäcke, H.; Döcke, W.-D.; Asadullah, K. Mechanisms involved in the side effects of glucocorticoids Pharmacol. Ther. 2002, 96, 23-43
4. McMaster, A.; Ray, D. W. Drug insight: selective agonists and antagonists of the glucocorticoid receptor Nat. Clin. Pract. Endocrinol. Metab. 2008, 4, 91-101
5. Zhou, J.; Cidlowski, J. A. The human glucocorticoid receptor: one gene, multiple proteins and diverse responses Steroids 2005, 70, 407-417
6. Adcock, I. M. Molecular mechanisms of glucocorticosteroid actions Pulm. Pharmacol. Ther. 2000, 13, 115-126
7. Heck, S.; Kullmann, M.; Gast, A.; Ponta, H.; Rahmsdorf, H. J.; Herrlich, P.; Cato, A. C. B. A distinct modulating domain in glucocorticoid receptor monomers in the repression of activity of the transcription factor AP-1 EMBO J. 1994, 13, 4087-4095
8. Katzenellenbogen, J. A.; Katzenellenbogen, B. S. Nuclear hormone receptors: ligand-activated regulators of transcription and diverse cell responses Chem. Biol. 1996, 3, 529-536
9. Resche-Rigon, M.; Gronemeyer, H. Therapeutic potential of selective modulators of nuclear receptor action Curr. Opin. Chem. Biol. 1998, 2, 501-507
10. Barnes, P. J. Anti-inflammatory actions of glucocorticoids: molecular mechanisms Clin. Sci. 1998, 94, 557-572
11. Buckbinder, L.; Robinson, R. P. The glucocorticoid receptor: molecular mechanism and new therapeutic opportunities Curr. Drug Targets: Inflammation Allergy 2002, 1, 127-136
12. Burnstein, K. L.; Cidlowski, J. A. The down side of glucocorticoid receptor regulation Mol. Cell. Endocrinol. 1992, 83, C1-C8
13. Reichardt, H. M.; Tuckermann, J. P.; Göttlicher, M.; Vujic, M.; Weih, F.; Angel, P.; Herrlich, P.; Schütz, G. Repression of inflammatory responses in the absence of DNA-binding by the glucocorticoid receptor EMBO J. 2002, 20, 7168-7173
14. Schäcke, H.; Berger, M.; Hansson, T. G.; McKerrecher, D.; Rehwinkel, H. Dissociated non-steroidal glucocorticoid receptor modulators: an update on new compounds Expert Opin. Ther. Pat. 2008, 18, 339
15. 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
16. Regan, J.; Razavi, H.; Thomson, D. Advances toward Dissociated Non-Steroidal Glucocorticoid Receptor Agonists. Annual Reports in Medicinal Chemistry; Doherty, A. M., Ed.; Academic Press: New York, 2008; Vol. 43, pp 141-154.
17. Mohler, M. L.; He, Y.; Wu, Z.; Hong, S.-S.; Miller, D. D. Dissociated non-steroidal glucocorticoids: tuning out untoward effects Expert Opin. Ther. Pat. 2007, 17, 37
18. Robinson, R. P.; Buckbinder, L.; Haugeto, A. I.; McNiff, P. A.; Millham, M. L.; Reese, M. R.; Schaefer, J. F.; Yocum, S. A. Octahydrophenanthrene-2,7- diol analogues as dissociated glucocorticoid receptor agonists: discovery and lead exploration J. Med. Chem. 2009, 52, 1731-1743
19. Berlin, M. Recent advances in the development of novel glucocorticoid receptor modulators Expert Opin. Ther. Pat. 2010, 20, 855-873
20. Manuscript in preparation. Bekkali, Y.; Betageri, R.; Emmanuel, M. J.; Hammach, A.; Harcken, H. J. J.; Kirrane, T. M.; Kuzmich, D.; Lee, T. W.; Liu, P.; Patel, U. R.; Razavi, H.; Riether, D.; Takahashi, H.; Thomson, D. S.; Wang, J.; Zindell, R.; Proudfoot, J. R. Preparation of Hydroxytrifluoromethyl- alkylpyrrolopyridines,-indoles, and Related Compounds as Modulators of Glucocorticoid Receptor Function. WO 2005030213, 2005.
21. Regan, J.; Lee, 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.; Pelletier, 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
22. 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 non-steroidal glucocorticoid receptor agonists Bioorg. Med. Chem. Lett. 2007, 17, 5025-5031 (Pubitemid 47259678)
23. Schäcke, H.; Schottelius, A.; Döcke, 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. Nat. Acad. Sci. U.S.A. 2004, 101, 227-232
24. Jaroch, S.; Rehwinkel, H.; Schäcke, H.; Schmees, N.; Skuballa, W.; Schneider, M.; Hubner, J.; Petrov, O. 5-Substituted Quinoline and Isoquinoline Derivatives, a Method for the Production Thereof and Their Use as Antiphlogistics. PCT Int. Appl. WO20050998, 2006.
25. 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
26. GLIDE, version 5.0; Schrödinger LLC: New York, 2008.
27. 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
28. Kelly, T. A.; Patel, U. R. J. Org. Chem. 1995, 60, 1875
29. Park, S. S.; Choi, J.-K.; Yum, E. K.; Ha, D.-C. A facile synthesis of 2,3-disubstituted pyrrolo[2,3-b ]pyridines via palladium-catalyzed heteroannulation with internal alkynes Tetrahedron Lett. 1998, 39, 627-630
30. Crous, R.; Dywer, C.; Holzapfel, C. W. Cross coupling strategies towards the synthesis of the streptonigrin CD moiety Heterocycles 1999, 51, 721
31. Kadnikov, D. V.; Larock, R. C. Synthesis of 2-quinolones via palladium-catalyzed carbonylative annulation of internal alkynes by N-substituted o-iodoanilines J. Org. Chem. 2004, 69, 6772-6780
32. Venuti, M. C.; Stephenson, R. A.; Alvarez, R.; Bruno, J. J.; Strosberg, A. M. Inhibitors of cyclic AMP phosphodiesterase. 3. Synthesis and biological evaluation of pyrido and imidazolyl analogues of 1,2,3,5-tetrahydro-2- oxoimidazo[2,1-b ]quinazoline J. Med. Chem. 1988, 31, 2136
33. Lee, T. W.; Proudfoot, J. R.; Thomson, D. S. A concise asymmetric route for the synthesis of a novel class of glucocorticoid mimetics containing a trifluoromethyl-substituted alcohol Bioorg. Med. Chem. Lett. 2006, 16, 654-657
34. Harcken, C.; Ward, Y.; Thomson, D.; Riether, D. A general and efficient synthesis of azaindoles and diazaindoles Synlett 2005, 20, 3121-3125
35. Waage, A.; Slupphaug, G.; Shalaby, R. Glucocorticoids inhibit the production of IL6 from monocytes, endothelial cells and fibroblasts Eur. J. Immunol. 1990, 20, 2439-2443
36. Bourguet, W.; Germain, P.; Gronemeyer, H. Nuclear receptor ligand-binding domains: three-dimensional structures, molecular interactions and pharmacological implications Trends Pharmacol. Sci. 2000, 21, 381-388
37. Bledsoe, R. K.; Stewart, E. L.; Pearce, K. H. Structure and function of the glucocorticoid receptor ligand binding domain Vitam. Horm. 2004, 68, 49-91
38. Madauss, K. P.; Bledsoe, R. K.; McLay, I.; Stewart, E. L.; Uings, I. J.; Weingarten, G.; Williams, S. P. The first X-ray crystal structure of the glucocorticoid receptor bound to a non-steroidal agonist Bioorg. Med. Chem. Lett. 2008, 18, 6097-6099
39. Biggadike, K.; Bledsoe, R. K.; Hassell, A. M.; Kirk, B. E.; McLay, I. M.; Shewchuk, L. M.; Stewart, E. L. X-ray crystal structure of the novel enhanced-affinity glucocorticoid agonist fluticasone furoate in the glucocorticoid receptor-ligand binding domain J. Med. Chem. 2008, 51, 3349-3352
40. 50 of 0.07 μM. In the aromatase induction assay, no increase in aromatase levels was observed, and thus, it was concluded that despite the ability of 37 to inhibit aromatase, the compound does not induce it.