Structure-activity relationships in human toll-like receptor 8-active 2,3-diamino-furo[2,3- c ]pyridines

Journal of Medicinal Chemistry

Volumn 55, Issue 18, 2012, Pages 8137-8151

  Salunke, Deepak B ^a   Yoo, Euna ^a   Shukla, Nikunj M ^a   Balakrishna, Rajalakshmi ^a   Malladi, Subbalakshmi S ^a   Serafin, Katelyn J ^a   Day, Victor W ^a   Wang, Xinkun ^a   David, Sunil A ^a  

^a UNIVERSITY OF KANSAS   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2,2' [HEXANE 1,6 DIYLBIS(AZANEDIYL)]BIS [7 METHYL 3 (PYRIDIN 2 YLAMINO)FURO[2,3 C]PYRIDINE 4,2 DIYL]DIMETHANOL; 2,3 DIAMINOFURO[2,3 C]PYRIDINE DERIVATIVE; [2 (BENZYLAMINO) 7 METHYL 3 (PHENYLAMINO)FURO[2,3 C]PYRIDIN 4 YL]METHANOL; [2 (BENZYLAMINO) 7 METHYL 3 (PYRAZIN 2 YLAMINO)FURO[2,3 C]PYRIDIN 4 YL]METHANOL; [2 (BENZYLAMINO) 7 METHYL 3 (PYRIDIN 2 YLAMINO)FURO[2,3 C]PYRIDIN 4 YL]METHANOL; [2 (BUTYLAMINO) 7 METHYL 3 (PYRIDIN 2 YLAMINO)FURO[2,3 C]PYRIDIN 4 YL]METHANOL; [2 (CYCLOHEXYLAMINO) 7 METHYL 3 (PYRAZIN 2 YLAMINO)FURO[2,3 C]PYRIDIN 4 YL]METHANOL; [2 (CYCLOHEXYLAMINO) 7 METHYL 3 (PYRIDIN 2 YLAMINO)FURO[2,3 C]PYRIDIN 4 YL]METHANOL; [2 (ISOPROPYLAMINO) 7 METHYL 3 (PYRIDIN 2 YLAMINO)FURO[2,3 C]PYRIDIN 4 YL]METHANOL; [2 (TERT BUTYLAMINO) 7 METHYL 3 (PYRAZIN 2 YLAMINO)FURO[2,3 C]PYRIDIN 4 YL]METHANOL; [2 (TERT BUTYLAMINO) 7 METHYL 3 (PYRIDIN 2 YLAMINO)FURO[2,3 C]PYRIDIN 4 YL]METHANOL; [2 [(2 CHLORO 6 METHYLPHENYL)AMINO] 7 METHYL 3 (PYRIDIN 2 YLAMINO)FURO[2,3 C]PYRIDIN 4 YL]METHANOL; [2 [(4 METHOXYPHENYL)AMINO] 7 METHYL 3 (PYRIDIN 2 YLAMINO)FURO[2,3 C]PYRIDIN 4 YL]METHANOL; [2 AMINO 7 METHYL 3 (PYRIDIN 2 YLAMINO)FURO[2,3-C]PYRIDIN 4 YL]METHANOL; [3 [(3 FLUOROPHENYL)AMINO] 7 METHYL 2 (PENTYLAMINO)FURO[2,3 C]PYRIDIN 4 YL]METHANOL; [5 (BENZYLOXY) 4 [3 (CYCLOHEXYLAMINO)IMIDAZO[1,2 A]PYRIDIN 2 YL] 6 METHYLPYRIDIN 3 YL]METHANOL; [7 METHYL 2 (PENTAN 2 YLAMINO) 3 (PYRIDIN 2 YLAMINO)FURO[2,3 C]PYRIDIN 4 YL]METHANOL; [7 METHYL 2 (PENTYLAMINO) 3 (PHENYLAMINO)FURO[2,3 C]PYRIDIN 4 YL]METHANOL; [7 METHYL 2 (PENTYLAMINO) 3 (PYRIDIN 2 YLAMINO)FURO[2,3 C]PYRIDIN 4 YL]METHANOL; [7 METHYL 2 [(1 PHENYLETHYL)AMINO] 3 (PYRIDIN 2 YLAMINO)FURO[2,3 C]PYRIDIN 4 YL]METHANOL; [7 METHYL 2 [(2 MORPHOLINOETHYL)AMINO] 3 (PYRIDIN 2YLAMINO)FURO[2,3 C]PYRIDIN 4 YL]METHANOL; [7 METHYL 3 (PYRIDIN 2 YLAMINO) 2 [(2,4,4 TRIMETHYLPENTAN 2 YL)AMINO]FURO[2,3 C]PYRIDIN 4 YL]METHANOL; [7 METHYL 3 (PYRIDIN 2 YLAMINO) 2 [[(TRIMETHYLSILYL)METHYL]AMINO]FURO[2,3 C]PYRIDIN 4 YL]METHANOL; [7 METHYL 3 [(3 NITROPHENYL)AMINO] 2 (PENTYLAMINO)FURO[2,3 C]PYRIDIN 4 YL]METHANOL; DIETHYL [[[4 (HYDROXYMETHYL) 7 METHYL 3 (PYRIDIN 2 YLAMINO)FURO[2,3 C]PYRIDIN 2 YL]AMINO]METHYL]PHOSPHONATE; ETHYL 2 [[4 (HYDROXYMETHYL) 7 METHYL 3 (PYRIDIN 2 YLAMINO)FURO[2,3 C]PYRIDIN 2 YL]AMINO]ACETATE; PYRIDINE DERIVATIVE; TERT BUTYL 3 [[4 (HYDROXYMETHYL) 7 METHYL 3 (PYRIDIN 2 YLAMINO)FURO[2,3 C]PYRIDIN 2 YL]AMINO]PROPANOATE; TOLL LIKE RECEPTOR 8; TOLL LIKE RECEPTOR AGONIST; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; CHEMICAL REACTION; CONTROLLED STUDY; CRYSTAL STRUCTURE; CYCLIZATION; DRUG STRUCTURE; EXPERIMENTAL RABBIT; FEMALE; GROEBKE BLACKBURN BIENAYME REACTION; HUMAN; HUMAN CELL; NONHUMAN; ONE POT SYNTHESIS; PERIPHERAL BLOOD MONONUCLEAR CELL; REPORTER GENE; SIGNAL TRANSDUCTION; STRUCTURE ACTIVITY RELATION; UPREGULATION;

ADJUVANTS, IMMUNOLOGIC; ANIMALS; DOSE-RESPONSE RELATIONSHIP, DRUG; FEMALE; HEK293 CELLS; HUMANS; LEUKOCYTES, MONONUCLEAR; PYRIDINES; RABBITS; STRUCTURE-ACTIVITY RELATIONSHIP; TOLL-LIKE RECEPTOR 8;

EID: 84866845441     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm301066h     Document Type: Article

References (56)

1. Iwasaki, A.; Medzhitov, R. Regulation of adaptive immunity by the innate immune system Science 2010, 327, 291-295
2. Iwasaki, A.; Medzhitov, R. Toll-like receptor control of the adaptive immune responses Nat. Immunol. 2004, 5, 987-995
3. Janeway, C. A., Jr.; Medzhitov, R. Innate immune recognition Annu. Rev. Immunol. 2002, 20, 197-216
4. Lee, M. S.; Kim, Y. J. Pattern-recognition receptor signaling initiated from extracellular, membrane, and cytoplasmic space Mol. Cells 2007, 23, 1-10
5. Seaton, B. A.; Crouch, E. C.; McCormack, F. X.; Head, J. F.; Hartshorn, K. L.; Mendelsohn, R. Review: Structural determinants of pattern recognition by lung collectins Innate Immun. 2010, 16, 143-150
6. Runza, V. L.; Schwaeble, W.; Mannel, D. N. Ficolins: novel pattern recognition molecules of the innate immune response Immunobiology 2008, 213, 297-306
7. Agrawal, A.; Singh, P. P.; Bottazzi, B.; Garlanda, C.; Mantovani, A. Pattern recognition by pentraxins Adv. Exp. Med. Biol. 2009, 653, 98-116
8. Bianchi, M. E. DAMPs, PAMPs and alarmins: all we need to know about danger J. Leukocyte Biol. 2007, 81, 1-5
9. Yoneyama, M.; Fujita, T. Function of RIG-I-like receptors in antiviral innate immunity J. Biol. Chem. 2007, 282, 15315-15318
10. Shaw, M. H.; Reimer, T.; Kim, Y. G.; Nunez, G. NOD-like receptors (NLRs): bona fide intracellular microbial sensors Curr. Opin. Immunol. 2008, 20, 377-382
11. Kawai, T.; Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors Nat. Immunol. 2010, 11, 373-384
12. Kumagai, Y.; Takeuchi, O.; Akira, S. Pathogen recognition by innate receptors J. Infect. Chemother. 2008, 14, 86-92
13. Takeda, K.; Akira, S. Toll-like receptors. Curr. Protoc. Immunol. 2007, Chapter 14, Unit.
14. Akira, S. Toll-like receptors and innate immunity Adv. Immunol. 1902, 78, 1-56
15. Akira, S.; Takeda, K.; Kaisho, T. Toll-like receptors: critical proteins linking innate and acquired immunity Nature Immunol. 2001, 2, 675-680
16. Cottalorda, A.; Verschelde, C.; Marcais, A.; Tomkowiak, M.; Musette, P.; Uematsu, S.; Akira, S.; Marvel, J.; Bonnefoy-Berard, N. TLR2 engagement on CD8 T cells lowers the threshold for optimal antigen-induced T cell activation Eur. J. Immunol. 2006, 36, 1684-1693
17. Kaisho, T.; Akira, S. Toll-like receptors as adjuvant receptors Biochim. Biophys. Acta 2002, 1589, 1-13
18. Wu, W.; Li, R.; Malladi, S. S.; Warshakoon, H. J.; Kimbrell, M. R.; Amolins, M. W.; Ukani, R.; Datta, A.; David, S. A. Structure-activity relationships in toll-like receptor-2 agonistic diacylthioglycerol lipopeptides J. Med. Chem. 2010, 53, 3198-3213
19. Agnihotri, G.; Crall, B. M.; Lewis, T. C.; Day, T. P.; Balakrishna, R.; Warshakoon, H. J.; Malladi, S. S.; David, S. A. Structure-activity relationships in toll-like receptor 2-agonists leading to simplified monoacyl lipopeptides J. Med. Chem. 2011, 54, 8148-8160
20. Salunke, D. B.; Shukla, N. M.; Yoo, E.; Crall, B. M.; Balakrishna, R.; Malladi, S. S.; David, S. A. Structure-Activity Relationships in Human Toll-like Receptor 2-Specific Monoacyl Lipopeptides J. Med. Chem. 2012, 55, 3353-3363
21. Liu, L.; Botos, I.; Wang, Y.; Leonard, J. N.; Shiloach, J.; Segal, D. M.; Davies, D. R. Structural basis of toll-like receptor 3 signaling with double-stranded RNA Science 2008, 320, 379-381
22. Uematsu, S.; Akira, S. Toll-like receptors and Type I interferons J. Biol. Chem. 2007, 282, 15319-15323
23. Rietschel, E. T.; Brade, H.; Brade, L.; Brandenburg, K.; Schade, U. F.; Seydel, U.; Zhringer, U.; Galanos, C.; Lderitz, O.; Westphal, O.; Labischinski, H.; Kusumoto, S.; Shiba, T. Lipid A, the endotoxic center of bacterial lipopolysaccharides: Relation of chemical structure to biological activity Prog. Clin. Biol. Res. 1987, 231, 25-53
24. Bowen, W. S.; Minns, L. A.; Johnson, D. A.; Mitchell, T. C.; Hutton, M. M.; Evans, J. T. Selective TRIF-dependent signaling by a synthetic toll-like receptor 4 agonist Sci. Signal. 2012, 5, ra13
25. Stover, A. G.; Da Silva, C. J.; Evans, J. T.; Cluff, C. W.; Elliott, M. W.; Jeffery, E. W.; Johnson, D. A.; Lacy, M. J.; Baldridge, J. R.; Probst, P.; Ulevitch, R. J.; Persing, D. H.; Hershberg, R. M. Structure-activity relationship of synthetic toll-like receptor 4 agonists J. Biol. Chem. 2004, 279, 4440-4449
26. Gerster, J. F.; Lindstrom, K. J.; Miller, R. L.; Tomai, M. A.; Birmachu, W.; Bomersine, S. N.; Gibson, S. J.; Imbertson, L. M.; Jacobson, J. R.; Knafla, R. T.; Maye, P. V.; Nikolaides, N.; Oneyemi, F. Y.; Parkhurst, G. J.; Pecore, S. E.; Reiter, M. J.; Scribner, L. S.; Testerman, T. L.; Thompson, N. J.; Wagner, T. L.; Weeks, C. E.; Andre, J. D.; Lagain, D.; Bastard, Y.; Lupu, M. Synthesis and structure-activity-relationships of 1H-imidazo[4,5-c]quinolines that induce interferon production J. Med. Chem. 2005, 48, 3481-3491
27. Shukla, N. M.; Malladi, S. S.; Mutz, C. A.; Balakrishna, R.; David, S. A. Structure-activity relationships in human toll-like receptor 7-active imidazoquinoline analogues J. Med. Chem. 2010, 53, 4450-4465
28. Shukla, N. M.; Mutz, C. A.; Malladi, S. S.; Warshakoon, H. J.; Balakrishna, R.; David, S. A. Toll-Like Receptor (TLR)-7 and -8 Modulatory Activities of Dimeric Imidazoquinolines J. Med. Chem. 2012, 55, 1106-1116
29. Hamilton, R. D.; Wynalda, M. A.; Fitzpatrick, F. A.; Teagarden, D. L.; Hamdy, A. H.; Snider, B. G.; Weed, S. D.; Stringfellow, D. A. Comparison between circulating interferon and drug levels following administration of 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone (ABPP) to different animal species J. Interferon Res. 1982, 2, 317-327
30. Stringfellow, D. A. Comparation interferon- inducing and antiviral properties of 2-amino-5-bromo-6-methyl-4-pyrimidinol (U-25,166), tilorone hydrochloride, and polyinosinic-polycytidylic acid Antimicrob. Agents Chemother. 1977, 11, 984-992
31. Lee, J.; Chuang, T. H.; Redecke, V.; She, L.; Pitha, P. M.; Carson, D. A.; Raz, E.; Cottam, H. B. Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: activation of Toll-like receptor 7 Proc. Natl. Acad. Sci. U. S. A 2003, 100, 6646-6651
32. Hirota, K.; Kazaoka, K.; Niimoto, I.; Kumihara, H.; Sajiki, H.; Isobe, Y.; Takaku, H.; Tobe, M.; Ogita, H.; Ogino, T.; Ichii, S.; Kurimoto, A.; Kawakami, H. Discovery of 8-hydroxyadenines as a novel type of interferon inducer J. Med. Chem. 2002, 45, 5419-5422
33. Isobe, Y.; Tobe, M.; Ogita, H.; Kurimoto, A.; Ogino, T.; Kawakami, H.; Takaku, H.; Sajiki, H.; Hirota, K.; Hayashi, H. Synthesis and structure-activity relationships of 2-substituted-8-hydroxyadenine derivatives as orally available interferon inducers without emetic side effects Bioorg. Med. Chem. 2003, 11, 3641-3647
34. Gorden, K. B.; Gorski, K. S.; Gibson, S. J.; Kedl, R. M.; Kieper, W. C.; Qiu, X.; Tomai, M. A.; Alkan, S. S.; Vasilakos, J. P. Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8 J. Immunol. 2005, 174, 1259-1268
35. Gorski, K. S.; Waller, E. L.; Bjornton-Severson, J.; Hanten, J. A.; Riter, C. L.; Kieper, W. C.; Gorden, K. B.; Miller, J. S.; Vasilakos, J. P.; Tomai, M. A.; Alkan, S. S. Distinct indirect pathways govern human NK-cell activation by TLR-7 and TLR-8 agonists Int. Immunol. 2006, 18, 1115-1126
36. Jin, M. S.; Lee, J. O. Structures of TLR-ligand complexes Curr. Opin. Immunol. 2008, 20, 414-419
37. Yoon, S. I.; Kurnasov, O.; Natarajan, V.; Hong, M.; Gudkov, A. V.; Osterman, A. L.; Wilson, I. A. Structural basis of TLR5-flagellin recognition and signaling Science 2012, 335, 859-864
38. Petrone, P. M.; Simms, B.; Nigsch, F.; Lounkine, E.; Kutchukian, P.; Cornett, A.; Deng, Z.; Davies, J. W.; Jenkins, J. L.; Glick, M. Rethinking Molecular Similarity: Comparing Compounds on the Basis of Biological Activity ACS Chem. Biol. 2012, 10.1021/cb3001028
39. Tsunoyama, K.; Amini, A.; Sternberg, M. J.; Muggleton, S. H. Scaffold hopping in drug discovery using inductive logic programming J. Chem. Inf. Model. 2008, 48, 949-957
40. Shukla, N. M.; Kimbrell, M. R.; Malladi, S. S.; David, S. A. Regioisomerism-dependent TLR7 agonism and antagonism in an imidazoquinoline Bioorg. Med. Chem. Lett. 2009, 19, 2211-2214
41. Shukla, N. M.; Mutz, C. A.; Ukani, R.; Warshakoon, H. J.; Moore, D. S.; David, S. A. Syntheses of fluorescent imidazoquinoline conjugates as probes of Toll-like receptor 7 Bioorg. Med. Chem. Lett. 2010, 20, 6384-6386
42. Shukla, N. M.; Lewis, T. C.; Day, T. P.; Mutz, C. A.; Ukani, R.; Hamilton, C. D.; Balakrishna, R.; David, S. A. Toward self-adjuvanting subunit vaccines: model peptide and protein antigens incorporating covalently bound toll-like receptor-7 agonistic imidazoquinolines Bioorg. Med. Chem. Lett. 2011, 21, 3232-3236
43. Baviskar, A. T.; Madaan, C.; Preet, R.; Mohapatra, P.; Jain, V.; Agarwal, A.; Guchhait, S. K.; Kundu, C. N.; Banerjee, U. C.; Bharatam, P. V. N-fused imidazoles as novel anticancer agents that inhibit catalytic activity of topoisomerase IIalpha and induce apoptosis in G1/S phase J. Med. Chem. 2011, 54, 5013-5030
44. Botos, I.; Segal, D. M.; Davies, D. R. The structural biology of Toll-like receptors Structure 2011, 19, 447-459
45. Jin, M. S.; Kim, S. E.; Heo, J. Y.; Lee, M. E.; Kim, H. M.; Paik, S. G.; Lee, H.; Lee, J. O. Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide Cell 2007, 130, 1071-1082
46. Hemmi, H.; Kaisho, T.; Takeuchi, O.; Sato, S.; Sanjo, H.; Hoshino, K.; Horiuchi, T.; Tomizawa, H.; Takeda, K.; Akira, S. Small anti-viral compounds activate immune cells via the TLR7MyD88-dependent signaling pathway Nat. Immunol. 2002, 3, 196-200
47. Weterings, J. J.; Khan, S.; van der Heden van Noort, G. J.; Melief, C. J.; Overkleeft, H. S.; van der Burg, S. H.; Ossendorp, F.; Van der Marel, G. A.; Filippov, D. V. 2-Azidoalkoxy-7-hydro-8-oxoadenine derivatives as TLR7 agonists inducing dendritic cell maturation Bioorg. Med. Chem. Lett. 2009, 19, 2249-2251
48. Kurimoto, A.; Hashimoto, K.; Nakamura, T.; Norimura, K.; Ogita, H.; Takaku, H.; Bonnert, R.; McInally, T.; Wada, H.; Isobe, Y. Synthesis and biological evaluation of 8-oxoadenine derivatives as toll-like receptor 7 agonists introducing the antedrug concept J. Med. Chem. 2010, 53, 2964-2972
49. Hood, J. D.; Warshakoon, H. J.; Kimbrell, M. R.; Shukla, N. M.; Malladi, S.; Wang, X.; David, S. A. Immunoprofiling toll-like receptor ligands: Comparison of immunostimulatory and proinflammatory profiles in ex vivo human blood models Hum. Vaccin. 2010, 6, 1-14
50. Warshakoon, H. J.; Hood, J. D.; Kimbrell, M. R.; Malladi, S.; Wu, W. Y.; Shukla, N. M.; Agnihotri, G.; Sil, D.; David, S. A. Potential adjuvantic properties of innate immune stimuli Hum. Vaccin. 2009, 5, 381-394
51. Kawai, T.; Akira, S. TLR signaling Semin. Immunol. 2007, 19, 24-32
52. Takeda, K.; Akira, S. TLR signaling pathways Semin. Immunol. 2004, 16, 3-9
53. Smirnov, D.; Schmidt, J. J.; Capecchi, J. T.; Wightman, P. D. Vaccine adjuvant activity of 3M-052: An imidazoquinoline designed for local activity without systemic cytokine induction Vaccine 2011, 29, 5434-5442
54. Ukani, R.; Lewis, T. C.; Day, T. P.; Wu, W.; Malladi, S. S.; Warshakoon, H. J.; David, S. A. Potent adjuvantic activity of a CCR1-agonistic bis-quinoline Bioorg. Med. Chem. Lett. 2012, 22, 293-295
55. + T cells AIDS Res. Human Retrovir. 2001, 17, 59-68
56. Kimbrell, M. R.; Warshakoon, H.; Cromer, J. R.; Malladi, S.; Hood, J. D.; Balakrishna, R.; Scholdberg, T. A.; David, S. A. Comparison of the immunostimulatory and proinflammatory activities of candidate Gram-positive endotoxins, lipoteichoic acid, peptidoglycan, and lipopeptides, in murine and human cells Immunol. Lett. 2008, 118, 132-141