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Current Topics in Medicinal Chemistry

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ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

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Review Article

Latest Advances in Small Molecule TLR 7/8 Agonist Drug Research

Author(s): David C. McGowan*

Volume 19, Issue 24, 2019

Page: [2228 - 2238] Pages: 11

DOI: 10.2174/1568026619666191009165418

Price: $65

Abstract

Toll-like receptors (TLRs) 7 and 8 play an important role in the activation of innate immune cells in mammals. These evolutionarily conserved receptors serve as important sentinels in response to infection. Activation of TLRs 7 and 8 triggers induction of a Th1 type innate immune response. The emergence of new structural and small molecule information generated in the last decade has contributed enormously to our understanding of this highly sophisticated process of innate immunity signaling. This review will focus on recent developments in the small molecule activation of TLR 7 and 8.

Keywords: Toll-Like Receptors, Innate Immunity, Protein-protein interface, P cell, Guanosine, Dendritic cells.

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[1]
Kawai, T.; Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol., 2010, 11(5), 373-384.
[http://dx.doi.org/10.1038/ni.1863] [PMID: 20404851]
[2]
Pasare, C.; Medzhitov, R. Toll-like receptors: linking innate and adaptive immunity. Microbes Infect., 2004, 6(15), 1382-1387.
[http://dx.doi.org/10.1016/j.micinf.2004.08.018] [PMID: 15596124]
[3]
a)Parker, L.C.; Prince, L.R.; Sabroe, I. Translational mini-review series on Toll-like receptors: networks regulated by Toll-like receptors mediate innate and adaptive immunity. Clin. Exp. Immunol., 2007, 147(2), 199-207.
[http://dx.doi.org/10.1111/j.1365-2249.2006.03203.x] [PMID: 17223959]
b)Akira, S.; Uematsu, S.; Takeuchi, O. Pathogen recognition and innate immunity. Cell, 2006, 124(4), 783-801.
[http://dx.doi.org/10.1016/j.cell.2006.02.015] [PMID: 16497588]
[4]
O’Neill, L.A. Immunology. After the toll rush. Science, 2004, 303(5663), 1481-1482.
[http://dx.doi.org/10.1126/science.1096113] [PMID: 15001768]
[5]
Zhu, G.; Xu, Y.; Cen, X.; Nandakumar, K.S.; Liu, S.; Cheng, K. Targeting pattern-recognition receptors to discover new small molecule immune modulators. Eur. J. Med. Chem., 2018, 144, 82-92.
[http://dx.doi.org/10.1016/j.ejmech.2017.12.026] [PMID: 29268133]
[6]
Bekeredjian-Ding, I.; Roth, S.I.; Gilles, S.; Giese, T.; Ablasser, A.; Hornung, V.; Endres, S.; Hartmann, G.; Cell-Independent, T. T cell-independent, TLR-induced IL-12p70 production in primary human monocytes. J. Immunol., 2006, 176(12), 7438-7446.
[http://dx.doi.org/10.4049/jimmunol.176.12.7438] [PMID: 16751389]
[7]
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(3), 1259-1268.
[http://dx.doi.org/10.4049/jimmunol.174.3.1259] [PMID: 15661881]
[8]
Xu, S.; Koldovsky, U.; Xu, M.; Wang, D.; Fitzpatrick, E.; Son, G.; Koski, G.; Czerniecki, B.J. High-avidity antitumor T-cell generation by toll receptor 8-primed, myeloid- derived dendritic cells is mediated by IL-12 production. Surgery, 2006, 140(2), 170-178.
[http://dx.doi.org/10.1016/j.surg.2006.03.006] [PMID: 16904966]
[9]
Moen, S.H.; Ehrnström, B.; Kojen, J.F.; Yurchenko, M.; Beckwith, K.S.; Afset, J.E.; Damås, J.K.; Hu, Z.; Yin, H.; Espevik, T.; Stenvik, J. Human toll-like receptor 8 (TLR8) is an important sensor of pyogenic bacteria, and is attenuated by cell surface TLR signaling. Front. Immunol., 2019, 10, 1209.
[http://dx.doi.org/10.3389/fimmu.2019.01209] [PMID: 31214180]
[10]
Coch, C.; Hommertgen, B.; Zillinger, T.; Daßler-Plenker, J.; Putschli, B.; Nastaly, M.; Kümmerer, B.M.; Scheunemann, J.F.; Schumak, B.; Specht, S.; Schlee, M.; Barchet, W.; Hoerauf, A.; Bartok, E.; Hartmann, G. Human TLR8 senses RNA From Plasmodium falciparum-infected red blood cells which is uniquely required for the IFN-γ response in NK cells. Front. Immunol., 2019, 10, 371.
[http://dx.doi.org/10.3389/fimmu.2019.00371] [PMID: 30972055]
[11]
Van Hoeven, N.; Fox, C.B.; Granger, B.; Evers, T.; Joshi, S.W.; Nana, G.I.; Evans, S.C.; Lin, S.; Liang, H.; Liang, L.; Nakajima, R.; Felgner, P.L.; Bowen, R.A.; Marlenee, N.; Hartwig, A.; Baldwin, S.L.; Coler, R.N.; Tomai, M.; Elvecrog, J.; Reed, S.G.; Carter, D. A Formulated TLR7/8 agonist is a flexible, highly potent and effective adjuvant for pandemic influenza vaccines. Sci. Rep., 2017, 7, 46426.
[http://dx.doi.org/10.1038/srep46426] [PMID: 28429728]
[12]
Gao, D.; Zeng, J.; Wang, X.; Liu, Y.; Li, W.; Hu, Y.; Gao, N.; Diao, Y.; Wang, Z.; Jiang, W.; Chen, J.; Jin, G. Conjugation of weak ligands with weak antigens to activate TLR-7: A step toward better vaccine adjuvants. Eur. J. Med. Chem., 2016, 120, 111-120.
[http://dx.doi.org/10.1016/j.ejmech.2016.04.070] [PMID: 27187863]
[13]
Gadd, A.J.; Greco, F.; Cobb, A.J.; Edwards, A.D. Targeted activation of toll-like receptors: conjugation of a toll-like receptor 7 agonist to a monoclonal antibody maintains antigen binding and specificity. Bioconjug. Chem., 2015, 26(8), 1743-1752.
[http://dx.doi.org/10.1021/acs.bioconjchem.5b00302] [PMID: 26133029]
[14]
Kim, H.; Niu, L.; Larson, P.; Kucaba, T.A.; Murphy, K.A.; James, B.R.; Ferguson, D.M.; Griffith, T.S.; Panyam, J. Polymeric nanoparticles encapsulating novel TLR7/8 agonists as immunostimulatory adjuvants for enhanced cancer immunotherapy. Biomaterials, 2018, 164, 38-53.
[http://dx.doi.org/10.1016/j.biomaterials.2018.02.034] [PMID: 29482062]
[15]
Cortez, A.; Li, Y.; Miller, A.T.; Zhang, X.; Yue, K.; Maginnis, J.; Hampton, J.; Hall, S.; Shapiro, M.; Nayak, B.; D’Oro, U.; Li, C.; Skibinski, D.; Mbow, M.L.; Singh, M.; O’Hagan, D.T.; Cooke, M.P.; Valiante, N.M.; Wu, T.Y. Incorporation of phosphonate into benzonaphthyridine toll-like receptor 7 agonists for adsorption to aluminum hydroxide. J. Med. Chem., 2016, 59(12), 5868-5878.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00489] [PMID: 27270029]
[16]
Dowling, D.J. Recent advances in the discovery and delivery of TLR7/8 agonists as vaccine adjuvants. Immunohorizons, 2018, 2(6), 185-197.
[http://dx.doi.org/10.4049/immunohorizons.1700063] [PMID: 31022686]
[17]
Ignacio, B.J.; Albin, T.J.; Esser-Kahn, A.P.; Verdoes, M. Toll-like receptor agonist conjugation: a chemical perspective. Bioconjug. Chem., 2018, 29(3), 587-603.
[http://dx.doi.org/10.1021/acs.bioconjchem.7b00808] [PMID: 29378134]
[18]
Tanji, H.; Ohto, U.; Shibata, T.; Miyake, K.; Shimizu, T. Structural reorganization of the Toll-like receptor 8 dimer induced by agonistic ligands. Science, 2013, 339(6126), 1426-1429.
[http://dx.doi.org/10.1126/science.1229159] [PMID: 23520111]
[19]
Kokatla, H.P.; Sil, D.; Tanji, H.; Ohto, U.; Malladi, S.S.; Fox, L.M.; Shimizu, T.; David, S.A. Structure-based design of novel human Toll-like receptor 8 agonists. ChemMedChem, 2014, 9(4), 719-723.
[http://dx.doi.org/10.1002/cmdc.201300573] [PMID: 24474703]
[20]
Yoo, E.; Salunke, D.B.; Sil, D.; Guo, X.; Salyer, A.C.D.; Hermanson, A.R.; Kumar, M.; Malladi, S.S.; Balakrishna, R.; Thompson, W.H.; Tanji, H.; Ohto, U.; Shimizu, T.; David, S.A. Determinants of activity at human Toll-like receptors 7 and 8: Quantitative structure-activity relationship (QSAR) of diverse heterocyclic scaffolds. J. Med. Chem., 2014, 57(19), 7955-7970.
[http://dx.doi.org/10.1021/jm500744f] [PMID: 25192394]
[21]
Ketloy, C.; Engering, A.; Srichairatanakul, U.; Limsalakpetch, A.; Yongvanitchit, K.; Pichyangkul, S.; Ruxrungtham, K. Expression and function of Toll-like receptors on dendritic cells and other antigen presenting cells from non-human primates. Vet. Immunol. Immunopathol., 2008, 125(1-2), 18-30.
[http://dx.doi.org/10.1016/j.vetimm.2008.05.001] [PMID: 18571243]
[22]
Zhang, Z.; Ohto, U.; Shibata, T.; Krayukhina, E.; Taoka, M.; Yamauchi, Y.; Tanji, H.; Isobe, T.; Uchiyama, S.; Miyake, K.; Shimizu, T. Structural analysis reveals that toll-like receptor 7 is a dual receptor for guanosine and single-stranded RNA. Immunity, 2016, 45(4), 737-748.
[http://dx.doi.org/10.1016/j.immuni.2016.09.011] [PMID: 27742543]
[23]
Tanji, H.; Ohto, U.; Shibata, T.; Taoka, M.; Yamauchi, Y.; Isobe, T.; Miyake, K.; Shimizu, T. Toll-like receptor 8 senses degradation products of single-stranded RNA. Nat. Struct. Mol. Biol., 2015, 22(2), 109-115.
[http://dx.doi.org/10.1038/nsmb.2943] [PMID: 25599397]
[24]
Geyer, M.; Pelka, K.; Latz, E. Synergistic activation of Toll-like receptor 8 by two RNA degradation products. Nat. Struct. Mol. Biol., 2015, 22(2), 99-101.
[http://dx.doi.org/10.1038/nsmb.2967] [PMID: 25650902]
[25]
Tanji, H.; Ohto, U.; Motoi, Y.; Shibata, T.; Miyake, K.; Shimizu, T. Autoinhibition and relief mechanism by the proteolytic processing of Toll-like receptor 8. Proc. Natl. Acad. Sci. USA, 2016, 113(11), 3012-3017.
[http://dx.doi.org/10.1073/pnas.1516000113] [PMID: 26929371]
[26]
Zhang, Z.; Ohto, U.; Shibata, T.; Taoka, M.; Yamauchi, Y.; Sato, R.; Shukla, N.M.; David, S.A.; Isobe, T.; Miyake, K.; Shimizu, T. Structural analyses of toll-like receptor 7 reveal detailed rna sequence specificity and recognition mechanism of agonistic ligands. Cell Rep., 2018, 25(12), 3371-3381.
[http://dx.doi.org/10.1016/j.celrep.2018.11.081] [PMID: 30566863]
[27]
Vieth, M.; Sutherland, J.J. Dependence of molecular properties on proteomic family for marketed oral drugs. J. Med. Chem., 2006, 49(12), 3451-3453.
[http://dx.doi.org/10.1021/jm0603825] [PMID: 16759087]
[28]
Huang, S.; Mei, H.; Zhang, D.; Ren, Y.; Kevin, M.; Pan, X. The emerging chemical patterns applied in predicting human toll-like receptor 8 agonists. MedChemComm, 2018, 9(11), 1961-1971.
[http://dx.doi.org/10.1039/C8MD00276B] [PMID: 30568763]
[29]
Kamath, P.; Darwin, E.; Arora, H.; Nouri, K. A review on imiquimod therapy and discussion on optimal management of basal cell carcinomas. Clin. Drug Investig., 2018, 38(10), 883-899.
[http://dx.doi.org/10.1007/s40261-018-0681-x] [PMID: 30128748]
[30]
Chamseddin, B.H.; Agim, N.G.; Jarin, J.; Wilson, E.E.; Mir, A. Therapy for anogenital verrucae in preadolescent children with topical and systemic treatment. Pediatr. Dermatol., 2019, 36(5), 623-627.
[http://dx.doi.org/10.1111/pde.13881] [PMID: 31197875]
[31]
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 TLR7 MyD88-dependent signaling pathway. Nat. Immunol., 2002, 3(2), 196-200.
[http://dx.doi.org/10.1038/ni758] [PMID: 11812998]
[32]
Pockros, P.J.; Guyader, D.; Patton, H.; Tong, M.J.; Wright, T.; McHutchison, J.G.; Meng, T.C. Oral resiquimod in chronic HCV infection: safety and efficacy in 2 placebo-controlled, double-blind phase IIa studies. J. Hepatol., 2007, 47(2), 174-182.
[http://dx.doi.org/10.1016/j.jhep.2007.02.025] [PMID: 17532523]
[33]
Tsitoura, D.; Ambery, C.; Price, M.; Powley, W.; Garthside, S.; Biggadike, K.; Quint, D. Early clinical evaluation of the intranasal TLR7 agonist GSK2245035: Use of translational biomarkers to guide dosing and confirm target engagement. Clin. Pharmacol. Ther., 2015, 98(4), 369-380.
[http://dx.doi.org/10.1002/cpt.157] [PMID: 26044169]
[34]
Boonstra, A.; Liu, B.S.; Groothuismink, Z.M.; Bergmann, J.F.; de Bruijne, J.; Hotho, D.M.; Hansen, B.E.; van Vliet, A.A.; van de Wetering de Rooij, J.; Fletcher, S.P.; Bauman, L.A.; Rahimy, M.; Appleman, J.R.; Freddo, J.L.; Reesink, H.W.; de Knegt, R.J.; Janssen, H.L. Potent immune activation in chronic hepatitis C patients upon administration of an oral inducer of endogenous interferons that acts via Toll-like receptor 7. Antivir. Ther. (Lond.), 2012, 17(4), 657-667.
[http://dx.doi.org/10.3851/IMP2023] [PMID: 22301364]
[35]
Qian, F.; Wang, X.; Zhang, L.; Lin, A.; Zhao, H.; Fikrig, E.; Montgomery, R.R. Impaired interferon signaling in dendritic cells from older donors infected in vitro with West Nile virus. J. Infect. Dis., 2011, 203(10), 1415-1424.
[http://dx.doi.org/10.1093/infdis/jir048] [PMID: 21398396]
[36]
Schlaepfer, E.; Audige, A.; Joller, H.; Speck, R. F. TLR7/8 triggering exerts opposing effects in acute versus latent HIV infection. J. Immunol. (Baltimore, Md. : 1950), 2006, 176(5), 2888-2895.
[37]
Ouaguia, L.; Leroy, V.; Dufeu-Duchesne, T.; Durantel, D.; Decaens, T.; Hubert, M.; Valladeau-Guilemond, J.; Bendriss-Vermare, N.; Chaperot, L.; Aspord, C. Circulating and hepatic BDCA1+, BDCA2+, and BDCA3+ dendritic cells are differentially subverted in patients with chronic HBV infection. Front. Immunol., 2019, 10, 112.
[http://dx.doi.org/10.3389/fimmu.2019.00112] [PMID: 30778353]
[38]
Ma, Z.; Zhang, E.; Yang, D.; Lu, M. Contribution of Toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses. Cell. Mol. Immunol., 2015, 12(3), 273-282.
[http://dx.doi.org/10.1038/cmi.2014.112] [PMID: 25418467]
[39]
Fidock, M.D.; Souberbielle, B.E.; Laxton, C.; Rawal, J.; Delpuech-Adams, O.; Corey, T.P.; Colman, P.; Kumar, V.; Cheng, J.B.; Wright, K.; Srinivasan, S.; Rana, K.; Craig, C.; Horscroft, N.; Perros, M.; Westby, M.; Webster, R.; van der Ryst, E. The innate immune response, clinical outcomes, and ex vivo HCV antiviral efficacy of a TLR7 agonist (PF-4878691). Clin. Pharmacol. Ther., 2011, 89(6), 821-829.
[http://dx.doi.org/10.1038/clpt.2011.60] [PMID: 21451504]
[40]
Li, L.; Barry, V.; Daffis, S.; Niu, C.; Huntzicker, E.; French, D.M.; Mikaelian, I.; Lanford, R.E.; Delaney, W.E., IV; Fletcher, S.P. Anti-HBV response to toll-like receptor 7 agonist GS-9620 is associated with intrahepatic aggregates of T cells and B cells. J. Hepatol., 2018, 68(5), 912-921.
[http://dx.doi.org/10.1016/j.jhep.2017.12.008] [PMID: 29247724]
[41]
Fosdick, A.; Zheng, J.; Pflanz, S.; Frey, C.R.; Hesselgesser, J.; Halcomb, R.L.; Wolfgang, G.; Tumas, D.B. Pharmacokinetic and pharmacodynamic properties of GS-9620, a novel Toll-like receptor 7 agonist, demonstrate interferon-stimulated gene induction without detectable serum interferon at low oral doses. J. Pharmacol. Exp. Ther., 2014, 348(1), 96-105.
[http://dx.doi.org/10.1124/jpet.113.207878] [PMID: 24133297]
[42]
Rebbapragada, I.; Birkus, G.; Perry, J.; Xing, W.; Kwon, H.; Pflanz, S. Molecular determinants of GS-9620-dependent TLR7 activation. PLoS One, 2016, 11(1)e0146835
[http://dx.doi.org/10.1371/journal.pone.0146835] [PMID: 26784926]
[43]
Niu, C.; Li, L.; Daffis, S.; Lucifora, J.; Bonnin, M.; Maadadi, S.; Salas, E.; Chu, R.; Ramos, H.; Livingston, C.M.; Beran, R.K.; Garg, A.V.; Balsitis, S.; Durantel, D.; Zoulim, F.; Delaney, W.E., IV; Fletcher, S.P. Toll-like receptor 7 agonist GS-9620 induces prolonged inhibition of HBV via a type I interferon-dependent mechanism. J. Hepatol., 2018, 68(5), 922-931.
[http://dx.doi.org/10.1016/j.jhep.2017.12.007] [PMID: 29247725]
[44]
Tsai, A.; Irrinki, A.; Kaur, J.; Cihlar, T.; Kukolj, G.; Sloan, D.D.; Murry, J.P. Toll-Like receptor 7 agonist GS-9620 induces HIV expression and HIV-specific immunity in cells from HIV-infected individuals on suppressive antiretroviral therapy. J. Virol., 2017, 91(8), e02166-e16.
[http://dx.doi.org/10.1128/JVI.02166-16] [PMID: 28179531]
[45]
Bam, R.A.; Hansen, D.; Irrinki, A.; Mulato, A.; Jones, G.S.; Hesselgesser, J.; Frey, C.R.; Cihlar, T.; Yant, S.R. TLR7 agonist GS-9620 is a potent inhibitor of acute hiv-1 infection in human peripheral blood mononuclear cells. Antimicrob. Agents Chemother., 2016, 61(1), e01369-e16.
[PMID: 27799218]
[46]
Daffis, S.; Morar, M.; Pattabiraman, D.; Voitenleitner, C.; Fletcher, S.; Javanbakht, H. Cytokine-dependent activation of MAIT cells by the TLR8 agonist GS-9688 but not the TLR7 agonist GS-9620. J. Hepatol., 2018, 68, S800.
[http://dx.doi.org/10.1016/S0168-8278(18)31872-5]
[47]
Schön, M.P.; Schön, M. TLR7 and TLR8 as targets in cancer therapy. Oncogene, 2008, 27(2), 190-199.
[http://dx.doi.org/10.1038/sj.onc.1210913] [PMID: 18176600]
[48]
Koga-Yamakawa, E.; Dovedi, S.J.; Murata, M.; Matsui, H.; Leishman, A.J.; Bell, J.; Ferguson, D.; Heaton, S.P.; Oki, T.; Tomizawa, H.; Bahl, A.; Takaku, H.; Wilkinson, R.W.; Harada, H. Intratracheal and oral administration of SM-276001: A selective TLR7 agonist, leads to antitumor efficacy in primary and metastatic models of cancer. Int. J. Cancer, 2013, 132(3), 580-590.
[http://dx.doi.org/10.1002/ijc.27691] [PMID: 22733292]
[49]
Cohen, P. A.; Northfelt, D. W.; Weiss, G. J.; Von Hoff, D. D.; Manjarrez, K.; Dietsch, G.; Hershberg, R. M.; Ramanathan, R. K. Phase I clinical trial of VTX-2337, a selective toll-like receptor 8 (TLR8) agonist, in patients with advanced solid tumors. J. Clin. Oncol., 2011, 29(15_suppl), 2537-2537.
[50]
Chow, L.Q.M.; Morishima, C.; Eaton, K.D.; Baik, C.S.; Goulart, B.H.; Anderson, L.N.; Manjarrez, K.L.; Dietsch, G.N.; Bryan, J.K.; Hershberg, R.M.; Disis, M.L.; Martins, R.G. Phase Ib trial of the toll-like receptor 8 agonist, motolimod (VTX-2337), combined with cetuximab in patients with recurrent or metastatic SCCHN. Clin. Cancer Res., 2017, 23(10), 2442-2450.
[http://dx.doi.org/10.1158/1078-0432.CCR-16-1934] [PMID: 27810904]
[51]
Zhao, B.G.; Vasilakos, J.P.; Tross, D.; Smirnov, D.; Klinman, D.M. Combination therapy targeting toll like receptors 7, 8 and 9 eliminates large established tumors. J. Immunother. Cancer, 2014, 2, 12.
[http://dx.doi.org/10.1186/2051-1426-2-12] [PMID: 24982761]
[52]
Gupta, S.; Tavakkoli, F.; Soukharev, S.; Gao, G.; Morris, S.R.; Miller, J.S. A phase 1, first-time-in-human study of MEDI9197, a TLR7/8 agonist, administered intratumorally in subjects with a solid tumor cancer. J. Clin. Oncol., 2016, 34, 3095-3095.
[http://dx.doi.org/10.1200/JCO.2016.34.15_suppl.TPS3095]
[53]
a)Basith, S.; Manavalan, B.; Lee, G.; Kim, S.G.; Choi, S. Toll-like receptor modulators: a patent review (2006-2010). Expert Opin. Ther. Pat., 2011, 21(6), 927-944.
[http://dx.doi.org/10.1517/13543776.2011.569494] [PMID: 21406035]
b)Hussein, W.M.; Liu, T.Y.; Skwarczynski, M.; Toth, I. Toll-like receptor agonists: a patent review (2011 - 2013). Expert Opin. Ther. Pat., 2014, 24(4), 453-470.
[http://dx.doi.org/10.1517/13543776.2014.880691] [PMID: 24456079]
[54]
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(10), 3481-3491.
[http://dx.doi.org/10.1021/jm049211v] [PMID: 15887957]
[55]
Li, L.; Guan, H. 2-amino-quinoline derivatives. WO2018196823, November 11. 2018.
[56]
Wu, T.; Li, Y.; Cortez, A.; Yue, K.; Zhang, X.; Singh, M.; Skibinski, D. D. Compounds and compositions as tlr activity modulators. WO2011049677, April 28,. 2011.
[57]
Singh, M.; Skibinski, D.; Cianetti, S.; Doro, F.; Jain, S. Immunogenic compositions including TLR activity modulators. WO2011027222, March 10,. 2011.
[58]
Chan, M.; Hayashi, T.; Mathewson, R.D.; Yao, S.; Gray, C.; Tawatao, R.I.; Kalenian, K.; Zhang, Y.; Hayashi, Y.; Lao, F.S.; Cottam, H.B.; Carson, D.A. Synthesis and characterization of PEGylated toll like receptor 7 ligands. Bioconjug. Chem., 2011, 22(3), 445-454.
[http://dx.doi.org/10.1021/bc1004813] [PMID: 21338093]
[59]
Bazin-Lee, H.; Johnson, D.A. Pegylated imidazoquinolines as tlr7 and tlr8 agonists. WO2017102652, June 22. 2017.
[60]
Chipman, S. D.; Demattei, J.; Kiwan, R.; Kachura, M.A. Alkyl chain modified imidazoquinoline tlr7/8 agonist compounds and uses thereof. WO2019040491, February 28,. 2019.
[61]
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(3), 1106-1116.
[http://dx.doi.org/10.1021/jm2010207] [PMID: 22239408]
[62]
Shukla, N.M.; Salunke, D.B.; Balakrishna, R.; Mutz, C.A.; Malladi, S.S.; David, S.A. Potent adjuvanticity of a pure TLR7-agonistic imidazoquinoline dendrimer. PLoS One, 2012, 7(8)e43612
[http://dx.doi.org/10.1371/journal.pone.0043612] [PMID: 22952720]
[63]
Larson, P.; Kucaba, T.A.; Xiong, Z.; Olin, M.; Griffith, T.S.; Ferguson, D.M. Design and synthesis of N1-modified imidazoquinoline agonists for selective activation of toll-like receptors 7 and 8. ACS Med. Chem. Lett., 2017, 8(11), 1148-1152.
[http://dx.doi.org/10.1021/acsmedchemlett.7b00256] [PMID: 29152046]
[64]
Shi, C.; Xiong, Z.; Chittepu, P.; Aldrich, C.C.; Ohlfest, J.R.; Ferguson, D.M. Discovery of imidazoquinolines with toll-like receptor 7/8 independent cytokine induction. ACS Med. Chem. Lett., 2012, 3(6), 501-504.
[http://dx.doi.org/10.1021/ml300079e] [PMID: 22837811]
[65]
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(25), 5419-5422.
[http://dx.doi.org/10.1021/jm0203581] [PMID: 12459008]
[66]
Biggadike, K.; Ahmed, M.; Ball, D.I.; Coe, D.M.; Dalmas Wilk, D.A.; Edwards, C.D.; Gibbon, B.H.; Hardy, C.J.; Hermitage, S.A.; Hessey, J.O.; Hillegas, A.E.; Hughes, S.C.; Lazarides, L.; Lewell, X.Q.; Lucas, A.; Mallett, D.N.; Price, M.A.; Priest, F.M.; Quint, D.J.; Shah, P.; Sitaram, A.; Smith, S.A.; Stocker, R.; Trivedi, N.A.; Tsitoura, D.C.; Weller, V. Discovery of 6-Amino-2-[(1S)-1-methylbutyl]oxy-9-[5-(1-piperidinyl)pentyl]-7,9-dihydro-8H-pu rin-8-one (GSK2245035), a highly potent and selective intranasal toll-like receptor 7 agonist for the treatment of asthma. J. Med. Chem., 2016, 59, 1711-1726.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01647] [PMID: 26861551]
[67]
Abbott, P.; Bonnert, R.; McInally, T.; Thom, S.; Wada, H.; Onuma, S. Purine derivatives. WO2012080730, June 21, . 2012.
[68]
Poudel, Y.B.; Gangwar, S.; Sivaprakasam, P.; Posy, S.L. 6-amino- 7,9-dihydro-8h-purin-8-one derivatives as immunostimulant tolllike receptor 7 (TLR7) agonists. WO2019036023, February 21,. 2019.
[69]
Bonfanti, J.-F.; Doublet, F.; Embrechts, W.; Fortin, J.; McGowan, D.; Muller, P.; Raboisson, P. Purine derivatives to treat viral infections. US2014323441, October 30,. 2014.
[70]
Young, I. S.; Gangwar, S.; Posy, S.; Poudel, Y.; Sivaprakasam, P. TOLL-like receptor 7 (TLR7) agonists having a tricyclic moiety, conjugates thereof, and methods and uses therefor. WO2019035969, February 21,. 2019.
[71]
He, L.; Gangwar, S.; Posy, S. L.; Poudel, Y. B.; Sivaprakasam, P. 6-amino-7,9-dihydro-8h-purin-8-one derivatives as immunostimulant toll-like receptor 7 (TLR7) agonists. WO2019035970, February 21. 2019.
[72]
He, L.; Gangwar, S.; Poudel, Y. B.; Sivaprakasam, P. 6-amino-7,9- dihydro-8H-purin-8-one derivatives as immunostimulant Toll-like receptor 7 agonists. WO2019035971, February 21. 2019.
[73]
Poudel, Y.B.; He, L.; Gangwar, S.; Posy, S.; Sivaprakasam, P. Amino-7,9-Dihydro-8H-PURIN-8-one derivatives as toll-like receptor 7 (TLR7) agonists as immunostimulants. WO2019035968, February 21. 2019.
[74]
Zhang, G.; Fei, H.; He, F.; Tao, W. Purinone derivative, preparation method thereof and application thereof in medicine. CN108948016, December 07,. 2018.
[75]
Bonfanti, J.-F.; Fortin, J.; Muller, P.; Doublet, F.; Raboisson, P.; Arnoult, E. Macrocyclic deaza-purinones for the treatment of viral infections. WO2014154859, October 02,. 2014.
[76]
Czarniecki, M. Small molecule modulators of toll-like receptors. J. Med. Chem., 2008, 51(21), 6621-6626.
[http://dx.doi.org/10.1021/jm800957k] [PMID: 18828583]
[77]
Carson, D. A.; Cottam, H. B.; Jin, G.; Wu, C.; Takabayashi, K. Purine analogs. US8846697, April 28. 2011.
[78]
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(7), 2964-2972.
[http://dx.doi.org/10.1021/jm100070n] [PMID: 20232824]
[79]
Biffen, M.; Matsui, H.; Edwards, S.; Leishman, A.J.; Eiho, K.; Holness, E.; Satterthwaite, G.; Doyle, I.; Wada, H.; Fraser, N.J.; Hawkins, S.L.; Aoki, M.; Tomizawa, H.; Benjamin, A.D.; Takaku, H.; McInally, T.; Murray, C.M. Biological characterization of a novel class of toll-like receptor 7 agonists designed to have reduced systemic activity. Br. J. Pharmacol., 2012, 166(2), 573-586.
[http://dx.doi.org/10.1111/j.1476-5381.2011.01790.x] [PMID: 22122192]
[80]
Krieg, A.M.; Vollmer, J. Toll-like receptors 7, 8, and 9: linking innate immunity to autoimmunity. Immunol. Rev., 2007, 220, 251-269.
[http://dx.doi.org/10.1111/j.1600-065X.2007.00572.x] [PMID: 17979852]
[81]
Engel, A.L.; Holt, G.E.; Lu, H. The pharmacokinetics of Toll-like receptor agonists and the impact on the immune system. Expert Rev. Clin. Pharmacol., 2011, 4(2), 275-289.
[http://dx.doi.org/10.1586/ecp.11.5] [PMID: 21643519]
[82]
Pryde, D.C.; Tran, T-D.; Jones, P.; Parsons, G.C.; Bish, G.; Adam, F.M.; Smith, M.C.; Middleton, D.S.; Smith, N.N.; Calo, F.; Hay, D.; Paradowski, M.; Proctor, K.J.W.; Parkinson, T.; Laxton, C.; Fox, D.N.A.; Horscroft, N.J.; Ciaramella, G.; Jones, H.M.; Duckworth, J.; Benson, N.; Harrison, A.; Webster, R. The discovery of a novel prototype small molecule TLR7 agonist for the treatment of hepatitis C virus infection. MedChemComm, 2011, 2, 185-189.
[http://dx.doi.org/10.1039/C0MD00197J]
[83]
Tran, T-D.; Pryde, D.C.; Jones, P.; Adam, F.M.; Benson, N.; Bish, G.; Calo, F.; Ciaramella, G.; Dixon, R.; Duckworth, J.; Fox, D.N.A.; Hay, D.A.; Hitchin, J.; Horscroft, N.; Howard, M.; Gardner, I.; Jones, H.M.; Laxton, C.; Parkinson, T.; Parsons, G.; Proctor, K.; Smith, M.C.; Smith, N.; Thomas, A. Design and optimisation of orally active TLR7 agonists for the treatment of hepatitis C virus infection. Bioorg. Med. Chem. Lett., 2011, 21(8), 2389-2393.
[http://dx.doi.org/10.1016/j.bmcl.2011.02.092] [PMID: 21419626]
[84]
Jones, P.; Pryde, D.; Tran, T. Imidazopyridinones. WO2009019553, February 12. 2009.
[85]
Ding, Z.; Wu, H.; Sun, F.; Wu, L.; Yang, L. Pyrrolopyrimidine compounds used as TLR7 agonist. WO2016023511, February 18, . 2016.
[86]
Ding, Z.; Sun, F.; Hu, Y.; Zhou, Y.; Wang, Z.; Yang, L. TLR7 agonist maleate salt, crystalline forms c, d and e thereof, preparation methods and uses of maleate salt and crystalline forms. WO2017133683, August 10, . 2017.
[87]
Ding, Z.; Sun, F.; Hu, Y.; Zhou, Y.; Zhao, R.; Yang, L. Method for preparing pyrrolo[3,2-d]pyrimidine compound, and intermediates thereof. WO2017133686, August 10, . 2017.
[88]
Ding, Z.; Sun, F.; Hu, Y.; Zhou, Y.; Wang, Z.; Zhao, R.; Yang, L. TLR7 agonist crystalline form a, preparation method and use thereof. WO2017133684, August 10,. 2017.
[89]
Ding, Z.; Sun, F.; Hu, Y.; Zhou, Y.; Wang, Z.; Zhao, R.; Yang, L. TLR7 agonist trifluoroacetate salt and crystalline form b thereof, preparation methods and uses. WO2017133687, August 10,. 2017.
[90]
Ding, Z.; Sun, F.; Wu, L.; Wu, H.; Chen, S.; Yang, L. 7- (THIAZOL-5-YL) pyrrolopyrimidine compound as tlr7 agonist. WO2017076346, May 11, . 2017.
[91]
Zhang, G.; Ma, D.; Yuan, H.; He, F.; Tao, W. Preparation of heteroaryl fused pyrazole derivative as TLR7 agonist. WO2018210298, Neovember 11. 2018.
[92]
Zhang, G.; Shu, C.; Hu, Q.; He, F.; Tao, W. Pyrazolo-heteroaryl derivative, preparation method and medical use thereof. WO2018095426, May 31,. 2018.
[93]
Liang, C.; Miao, K.; Shen, H.; Yun, H. Novel cyclicsulfonimidoylpurinone compounds and derivatives for the treatment and prophylaxis of virus infection. WO2018078149, May 03 . 2018.
[94]
Gao, L.; Liang, C.; Yun, H.; Zheng, X.; Wang, J.; Miao, K.; Zhang, B. B. 7-substituted sulfonimidoylpurinone compounds for the treatment and prophylaxis of virus infection. WO2018041763, March 08, . 2018.
[95]
Roethle, P.A.; McFadden, R.M.; Yang, H.; Hrvatin, P.; Hui, H.; Graupe, M.; Gallagher, B.; Chao, J.; Hesselgesser, J.; Duatschek, P.; Zheng, J.; Lu, B.; Tumas, D.B.; Perry, J.; Halcomb, R.L. Identification and optimization of pteridinone Toll-like receptor 7 (TLR7) agonists for the oral treatment of viral hepatitis. J. Med. Chem., 2013, 56(18), 7324-7333.
[http://dx.doi.org/10.1021/jm400815m] [PMID: 23961878]
[96]
Desai, M. C.; Halcomb, R. L.; Hrvatin, P.; Hui, H.; McFadden, R.; Roethle, P. A.; Yang, H. Modulators of toll-like receptors. US20100143301, June 10, . 2010.
[97]
Geleziunas, R.; Hesselgesser, J. Modulators of toll-like receptors for the treatment of HIV. WO2016007765, January 14, . 2016.
[98]
Andres, P. Solid forms of a toll-like receptor modulator. WO2016044182, March 24, . 2016.
[99]
Bondy, S.S.; McFadden, R. Deuterated toll-like receptor modulators. WO2017035230, March 03, 2017.
[100]
Liu, G.; Yu, H.; Chen, Q.; Kang, X.; Luo, X.; Jiang, Y.; Zeng, H.; Song, H.; Liu, R.; Wang, L. Dihydro pteridinone derivative, preparation method therefor, and application thereof. WO2017219931, December 28 . 2017.
[101]
Cortez, A.; Li, Y.; Liao, X. Compounds and compositions as tlr-7 activity modulators. WO2011057148, May 11, . 2011.
[102]
Zhang, G.; Chen, Y.; Huang, Z.; He, F.; Tao, W. Condensed ring based ketone derivatives, preparation method thereof and application of derivatives in medicin. CN108794486, November 13,. 2018.
[103]
Fujita, H.; Antoku, F.; Fujiwara, N.; Iwai, K.; Tanaka, H.; Kawakami, H. H. Pyrimidine derivatives. WO2000012487, March 09, 2000.
[104]
Bennett, N.; McInally, T.; Thom, S. Novel pyrimidine derivatives and their use in the treatment of cancer and further diseases. WO2010133885, November 25, . 2010.
[105]
Bailey, A.; Highton, A.; McInally, T.; Mochel, T.; Urabe, D. Phenol compounds als toll -like receptor 7 agonists. WO2012066335, May 24, . 2012.
[106]
McInally, T.; Mochel, T.; Hasegawa, F.; Hori, S. Benzylamine compounds as toll -like receptor 7 agonists. WO2012066336, May 24, . 2012.
[107]
Tosaki, S.; Hori, S. Cyclic amide compounds and their use in the treatment of disease. WO2012067268, May 24 2012.
[108]
Hori, S.; Hasegawa, F.; Urabe, D.; Kurebayashi, H. Carboxylic acid compounds. WO2013172479, November 11 2013.
[109]
Beesu, M.; Salyer, A.C.D.; Trautman, K.L.; Hill, J.K.; David, S.A. Human toll-like receptor (TLR) 8-specific agonistic activity in substituted pyrimidine-2,4-diamines. J. Med. Chem., 2016, 59(17), 8082-8093.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00872] [PMID: 27513008]
[110]
Beesu, M.; Salyer, A.C.D.; Brush, M.J.H.; Trautman, K.L.; Hill, J.K.; David, S.A. Identification of high-potency human TLR8 and dual TLR7/TLR8 agonists in pyrimidine-2,4-diamines. J. Med. Chem., 2017, 60(5), 2084-2098.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01860] [PMID: 28146629]
[111]
McGowan, D.; Herschke, F.; Pauwels, F.; Stoops, B.; Last, S.; Pieters, S.; Scholliers, A.; Thoné, T.; Van Schoubroeck, B.; De Pooter, D.; Mostmans, W.; Khamlichi, M.D.; Embrechts, W.; Dhuyvetter, D.; Smyej, I.; Arnoult, E.; Demin, S.; Borghys, H.; Fanning, G.; Vlach, J.; Raboisson, P. Novel pyrimidine toll-like receptor 7 and 8 dual agonists to treat hepatitis B virus. J. Med. Chem., 2016, 59(17), 7936-7949.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00747] [PMID: 27513093]
[112]
McGowan, D. C.; Raboisson, P.; Embrechts, W.; Jonckers, T.; Last, S.; Pieters, S.; Vlach, J. Pyrimidine derivatives for the treatment of viral infections. WO2012136834, October 11, 2012.
[113]
Gembus, V.; Jubault, H.; Levacher, V.; Bonfanti, J.-F.; McGowan, D. C.; Guillemont, J. 1,2,4-Triazine derivatives for the treatment of viral infections. WO2014053516, April 10, 2014.
[114]
McGowan, D. C.; Pieters, S.; Embrechts, W.; Last, S.; Jonckers, T.; Raboisson, P. Acylaminopyrimidine derivatives for the treatment of viral infections and further diseases. WO2014053595, April 10,. 2014.
[115]
McGowan, D. C.; Guillemont, J.; Stoops, B.; Herschke, F.; Jonckers, T.; Bollekens, J.; Calmus, L.; Raboisson, P. Pyrimidine Prodrugs for the treatment of viral infections and further diseases. WO2018060317, April 05, . 2018.
[116]
David, S.A.; Beesu, M. Pyrimidines as toll-like receptor agonists and their preparation and use to inhibit immune response. US20180215720. August 02, . 2018.
[117]
McGowan, D.C.; Herschke, F.; Khamlichi, M.D.; Rosauro, M.L.; Benedicto, S.M.P.; Pauwels, F.; Stoops, B.; Pande, V.; Scholliers, A.; Van Schoubroeck, B.; Mostmans, W.; Van Dijck, K.; Thoné, T.; Horton, H.; Fanning, G.; Jonckers, T.H.M.; Raboisson, P. Design and synthesis of tetrahydropyridopyrimidine based Toll-Like Receptor (TLR) 7/8 dual agonists. Bioorg. Med. Chem. Lett., 2018, 28(19), 3216-3221.
[http://dx.doi.org/10.1016/j.bmcl.2018.08.015] [PMID: 30143425]
[118]
McGowan, D.C.; Raboisson, P.; Jonckers, T. Piperidino-pyrimidine derivatives for the treatment of viral infections. WO2013117615, August 15. 2013.
[119]
Embrechts, W.; Herschke, F.; Pauwels, F.; Stoops, B.; Last, S.; Pieters, S.; Pande, V.; Pille, G.; Amssoms, K.; Smyej, I.; Dhuyvetter, D.; Scholliers, A.; Mostmans, W.; Van Dijck, K.; Van Schoubroeck, B.; Thone, T.; De Pooter, D.; Fanning, G.; Jonckers, T.H.M.; Horton, H.; Raboisson, P.; McGowan, D. 2,4-diaminoquinazolines as dual toll-like receptor (TLR) 7/8 modulators for the treatment of hepatitis B virus. J. Med. Chem., 2018, 61(14), 6236-6246.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00643] [PMID: 29965759]
[120]
McGowan, D. C.; Raboisson, P.; Jonckers, T.; Last, S.; Embrechts, W.; Pieters, S. Quinazoline derivatives for the treatment of viral infections and further diseases. WO2012156498, November 22 2012.
[121]
Last, S.; McGowan, D. C.; Raboisson, P.; Jonckers, T.; Embrechts, W.; Pieters, S. Heterocyclic substituted 2-amino-quinazoline derivatives for the treatment of viral infections. WO2014076221, November 22 . 2012.
[122]
McGowan, D.C.; Herschke, F.; Pauwels, F.; Stoops, B.; Smyej, I.; Last, S.; Pieters, S.; Embrechts, W.; Khamlichi, M.D.; Thoné, T.; Van Schoubroeck, B.; Mostmans, W.; Wuyts, D.; Verstappen, D.; Scholliers, A.; De Pooter, D.; Dhuyvetter, D.; Borghys, H.; Tuefferd, M.; Arnoult, E.; Hong, J.; Fanning, G.; Bollekens, J.; Urmaliya, V.; Teisman, A.; Horton, H.; Jonckers, T.H.M.; Raboisson, P. Identification and optimization of Pyrrolo[3,2-d]pyrimidine toll-like receptor 7 (TLR7) selective agonists for the treatment of hepatitis B. J. Med. Chem., 2017, 60(14), 6137-6151.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00365] [PMID: 28671847]
[123]
McGowan, D.C.; Embrechts, W.; Pieters, S.; Last, S.; Jonckers, T.; Raboisson, P. Pyrrolo[3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases. WO2014207082, December 31 2014.
[124]
McGowan, D. C.; Last, S.; Pieters, S.; Embrechts, W.; Jonckers, T.; Raboisson, P. Pyrrolo[3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases. WO2014056953, April 17 . 2014.
[125]
McGowan, D. C.; Raboisson, P. Thieno[3,2-d]pyrimidines derivatives for the treatment of viral infections. WO2015014815, February 05, . 2015.
[126]
Ding, C. Z.; Cai, Z.; Sun, F.; Hu, G.; Li, J.; Chen, S. Isothiazolo[ 4,3-d]pyrimidine-5,7-diamine derivative as TLR8 agonists. WO2018233648, December 27, . 2018.
[127]
McGowan, D. C.; Embrechts, W; Guillemont, J.; Jonckers, T.; Raboisson, P. Dihydropyranopyrimidines for the treatment of viral infections. WO2018002319, January 04, 2018.
[128]
Aktoudianakis, E.; Chin, G.; Mackman, R.; Metobo, S.; Mish, M.; Pyun, H.; Zablocki, J. Toll-like receptor modulating 4,6-diaminopyrido[ 3,2-d]pyrimidine compounds. WO2016141092, September 09, 2016.
[129]
Chin, G.; Mackman, R.; Mish, M.; Zablocki, J. Toll-like receptor modulator compounds. WO2018045144, March 08, . 2018.
[130]
Dohrety, G.; Eary, T.; Groneberg, R.; Jones, Z. 8-Substituted benzoazepines as Toll-like receptor modulators. WO2007024612, March 01, 2007.
[131]
Howbert, J.; Duvvuri, M.; Hershberg, R.; Dietsch, G. Toll-like receptor agonist formulations and their use. WO2010014913, Feb 4, 2010.
[132]
Howbert, J.; Kusukuntla, V.; Tretyakov, A.; Nielson, N.; Krasik, P.; Jiang, J.; Yang, H. Methods of synthesis of benzoazepine derivatives. WO2010054215, May 14, 2010.
[133]
Howbert, J.; Dietsch, G.; Hershberg, R.; Burgess, L.; Lyssikatos, J. P.; Newhouse, B.; Yang, H. Preparation of substituted benzoazepines as toll-like receptor modulators. WO2011022508, February 24, . 2011.
[134]
Howbert, J.; Dietsch, G.; Hershberg, R.; Burgess, L.; Dohrety, G.; Eary, T.; Groneberg, R.; Jones, Z. Substituted benzoazepines as Toll-like receptor modulators. WO2011022509, February 24. 2012.
[135]
Howbert, J.; Hershberg, R. Substituted benzoazepines as Toll-like receptor modulators. WO2012097177, July 19, 2012.
[136]
Howbert, J.; Hershberg, R. Substituted benzoazepines as Toll-like receptor modulators. WO2012097173, July 19, . 2012.
[137]
Hoves, S.; Koerner, M.; Wang, L.; Yun, H.; Zhu, W.; Zhang, W. Preparation of benzazepine sulfonamide compounds as TLR agonists. WO20160967, June 23, 2016.
[138]
Hoves, S.; Wang, L.; Yun, H.; Zhang, W.; Zhu, W. Preparation of benzazepine dicarboxamide compounds as TLR agonists. WO2016142250, September 15, 2016.
[139]
Wang, L.; Yun, H.; Zhang, W.; Zhu, W.; Zhang, Z. Preparation of benzazepine dicarboxamide as TLR8 agonists for treatment of autoimmune disease, cancer, and other diseases. WO2017202704, November 30 2017.
[140]
Wang, L.; Yun, H.; Zhang, W.; Zhu, W.; Zhang, Z. Preparation of benzazepine dicarboxamide as TLR8 agonists for treatment of autoimmune disease, cancer, and other diseases. WO2017202703, November 30 2017.
[141]
Dey, F.; Wang, L.; Yun, H.; Zhang, W.; Zhang, Z.; Zhu, W. Preparation of dihydropyrimidinyl benzazepine carboxamide compounds as TLR8 agonists. WO2017216054, December 21 2017.
[142]
Hoves, S.; Wang, L.; Yun, H.; Zhang, W.; Zhu, W. Preparation of sulfinylphenyl and sulfonimidoylphenyl benzazepines as TLR agonists. WO2017046112, March 23 2017.
[143]
Gao, D.; Li, W.; Chen, Y.; Wei, C.; Wang, Y.; Luo, X. Purinescaffold TLR7 ligands and conjugate thereof. WO2017197624, November 23, 2017.
[144]
Horsmans, Y.; Berg, T.; Desager, J.P.; Mueller, T.; Schott, E.; Fletcher, S.P.; Steffy, K.R.; Bauman, L.A.; Kerr, B.M.; Averett, D.R. Isatoribine, an agonist of TLR7, reduces plasma virus concentration in chronic hepatitis C infection. Hepatology, 2005, 42(3), 724-731.
[http://dx.doi.org/10.1002/hep.20839] [PMID: 16116638]
[145]
Kini, G.D.; Anderson, J.D.; Sanghvi, Y.S.; Lewis, A.F.; Smee, D.F.; Revankar, G.R.; Robins, R.K.; Cottam, H.B. Synthesis and antiviral activity of certain guanosine analogues in the thiazolo[4,5-d]pyrimidine ring system. J. Med. Chem., 1991, 34(10), 3006-3010.
[http://dx.doi.org/10.1021/jm00114a008] [PMID: 1656042]
[146]
Smee, D.F.; Alaghamandan, H.A.; Cottam, H.B.; Sharma, B.S.; Jolley, W.B.; Robins, R.K. Broad-spectrum in vivo antiviral activity of 7-thia-8-oxoguanosine, a novel immunopotentiating agent. Antimicrob. Agents Chemother., 1989, 33(9), 1487-1492.
[http://dx.doi.org/10.1128/AAC.33.9.1487] [PMID: 2817849]
[147]
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. USA, 2003, 100(11), 6646-6651.
[http://dx.doi.org/10.1073/pnas.0631696100] [PMID: 12738885]
[148]
Liu, H.; Wu, G.; Yun, H. Preparation of novel oxathiolane carboxylic acids and derivatives for the treatment and prophylaxis of virus infection. WO2016180691, November 17, . 2016.
[149]
Feng, S.; Liu, H.; Wu, G.; Yun, H.; Chen, D.; Li, C. Compounds for use in the treatment of infectious diseases. WO2016055553, April 14, . 2016.
[150]
Wang, B.; Wang, L.; Yun, H.; Zheng, X. Novel substituted aminothiazolopyrimidinedione for the treatment and prophylaxis of virus infection. WO2016180743, November 17 . 2016.
[151]
Chen, D.; Feng, S.; Gao, L.; Li, C.; Wang, B.; Wang, L.; Yun, H.; Zheng, X. 3-substituted 5-amino-6h-thiazolo[4,5-d]pyrimidine-2,7- dione compounds for the treatment and prophylaxis of virus infection. WO2016091698, June 16, . 2016.
[152]
Salunke, D.B.; Yoo, E.; Shukla, N.M.; Balakrishna, R.; Malladi, S.S.; Serafin, K.J.; Day, V.W.; Wang, X.; David, S.A. Structure-activity relationships in human Toll-like receptor 8-active 2,3-diamino-furo[2,3-c]pyridines. J. Med. Chem., 2012, 55(18), 8137-8151.
[http://dx.doi.org/10.1021/jm301066h] [PMID: 22924757]
[153]
Beesu, M.; Caruso, G.; Salyer, A.C.; Shukla, N.M.; Khetani, K.K.; Smith, L.J.; Fox, L.M.; Tanji, H.; Ohto, U.; Shimizu, T.; David, S.A. Identification of a Human Toll-Like Receptor (TLR) 8-Specific Agonist and a Functional Pan-TLR Inhibitor in 2-Aminoimidazoles. J. Med. Chem., 2016, 59(7), 3311-3330.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00023] [PMID: 26966993]
[154]
Lipford, G. B.; Nguyen, T.; Zepp, C. Triazole compounds as tolllike receptor (TLR) agonists. WO2009030996, March 12. 2009.
[155]
David, S.A.; Kokatla, H.; Sil, D.; Malladi, S.; Fox, L.M. Toll-like receptor 8 agonists. WO2015095780, June 25. 2015.
[156]
David, S.; Yoo, E.; Shukla, N.; Salyer, A. C.; Beesu, M.; Malladi, S.S.; Jones, C. Toll-like receptor agonists. WO2015023958, February 19,. 2015.
[157]
Chae, H.; Lim, D.; Choi, B.; Cho, Y. Anti-viral agent having immunological enhancement effect and screening method thereof. KR2016137897A.
[158]
Shukla, N.M.; Chan, M.; Hayashi, T.; Carson, D.A.; Cottam, H.B. Recent advances and perspectives in small-molecule TLR ligands and their modulators. ACS Med. Chem. Lett., 2018, 9(12), 1156-1159.
[http://dx.doi.org/10.1021/acsmedchemlett.8b00566] [PMID: 30613317]

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