Discovery of non-peptide small molecular CXCR4 antagonists as anti-HIV agents: Recent advances and future opportunities

European Journal of Medicinal Chemistry

Volumn 114, Issue , 2016, Pages 65-78

  Zhang, Heng ^a   Kang, Dongwei ^a   Huang, Boshi ^a   Liu, Na ^a   Zhao, Fabao ^a   Zhan, Peng ^a   Liu, Xinyong ^a  

^a SHANDONG UNIVERSITY   (China)

Author keywords

AIDS; CXCR4; Drug design; Entry inhibitors; HIV 1; Small molecular

Indexed keywords

8 [(4 AMINOBUTYL)(2 BENZIMIDAZOLYLMETHYL)AMINO] 1,2,3,4 TETRAHYDROQUINOLINE; ALPHA N ACETYLNONA DEXTRO ARGININE AMIDE; ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; CHEMOKINE RECEPTOR CXCR4; CHEMOKINE RECEPTOR CXCR4 ANTAGONIST; CYCLOPEPTIDE; INDOLE DERIVATIVE; PIPERIDINE DERIVATIVE; PLERIXAFOR; CXCR4 PROTEIN, HUMAN; MOLECULAR LIBRARY;

ACQUIRED IMMUNE DEFICIENCY SYNDROME; ANTIVIRAL ACTIVITY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1 INFECTION; NONHUMAN; PROTEIN FUNCTION; PROTEIN STRUCTURE; RETICULOENDOTHELIAL SYSTEM; REVIEW; STRUCTURE ACTIVITY RELATION; ANTAGONISTS AND INHIBITORS; CHEMICAL STRUCTURE; CHEMISTRY; DRUG DEVELOPMENT; DRUG EFFECTS; HUMAN IMMUNODEFICIENCY VIRUS; MICROBIAL SENSITIVITY TEST; MOLECULAR LIBRARY; PHARMACOLOGY; SYNTHESIS;

ANTI-HIV AGENTS; DRUG DISCOVERY; HIV; HUMANS; MICROBIAL SENSITIVITY TESTS; MOLECULAR STRUCTURE; RECEPTORS, CXCR4; SMALL MOLECULE LIBRARIES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84964308427     PISSN: 02235234     EISSN: 17683254     Source Type: Journal    
DOI: 10.1016/j.ejmech.2016.02.051     Document Type: Short Survey

References (69)

1. http://www.who.int/campaigns/aids-day/2015/en/.
2. T. Murakami, N. Yamamoto, Role of CXCR4 in HIV infection and its potential as a therapeutic target, Future Microbiol. 5 (2010) 1025-1039.
3. A. Flores, E. Quesada, Entry inhibitors directed towards glycoprotein gp120: an overview on a promising target for HIV-1 therapy, Curr. Med. Chem. 20 (2013) 751-771.
4. Y. Mehellou, E. De Clercq, Twenty-six years of anti-HIV drug discovery: where do we stand and where do we go? J. Med. Chem. 53 (2010) 521-538.
5. E. De Clercq, Anti-HIV drugs: 25 compounds approved within 25 years after the discovery of HIV, Int. J. Antimicrob. Agents 33 (2009) 307-320.
6. Y. Feng, C.C. Broder, P.E. Kennedy, E.A. Berger, HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor, Science 272 (1996) 872-877.
7. E. De Clercq, N. Yamamoto, R. Pauwels, M. Baba, D. Schols, H. Nakashima, J. Balzarini, Z. Debyser, B.A. Murrer, D. Schwartz, Potent and selective inhibition of human immunodeficiency virus (HIV)-1 and HIV-2 replication by a class of bicyclams interacting with a viral uncoating event, Proc. Natl. Acad. Sci. U. S. A. 89 (1992) 5286-5290.
8. E. De Clercq, Inhibition of HIV infection by bicyclams, highly potent and specific CXCR4 antagonists, Mol. Pharmacol. 57 (2000) 833-839.
9. A. Khan, J. Greenman, S.J. Archibald, Small molecule CXCR4 chemokine receptor antagonists: developing drug candidates, Curr. Med. Chem. 14 (2007) 2257-2277.
10. J. Pease, R. Horuk, Chemokine receptor antagonists, J. Med. Chem. 55 (2012) 9363-9392.
11. B. Wu, E.Y. Chien, C.D. Mol, G. Fenalti, W. Liu, V. Katritch, R. Abagyan, A. Brooun, P. Wells, F.C. Bi, Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists, Science 330 (2010) 1066-1071.
12. J.M. Busillo, J.L. Benovic, Regulation of CXCR4 signaling, Biochim. Biophys. Acta 1768 (2007) 952-963.
13. A. Sodhi, S. Montaner, J.S. Gutkind, Viral hijacking of G-protein-coupled-receptor signalling networks, Nat. Rev. Mol. Cell Biol. 5 (2004) 998-1012.
14. P.M. Murphy, The molecular biology of leukocyte chemoattractant receptors, Annu. Rev. Immunol. 12 (1994) 593-633.
15. B. Debnath, S. Xu, F. Grande, A. Garofalo, N. Neamati, Small molecule inhibitors of CXCR4, Theranostics 3 (2013) 47-75.
16. J.J. Onuffer, R. Horuk, Chemokines, chemokine receptors and small-molecule antagonists: recent developments, Trends Pharmacol. Sci. 23 (2002) 459-467.
17. B.J. Doranz, K. Grovit-Ferbas, M.P. Sharron, S.-H. Mao, M.B. Goetz, E.S. Daar, R.W. Doms, W.A. O'Brien, A small-molecule inhibitor directed against the chemokine receptor CXCR4 prevents its use as an HIV-1 coreceptor, J. Exp. Med. 186 (1997) 1395-1400.
18. T. Murakami, T. Nakajima, Y. Koyanagi, K. Tachibana, N. Fujii, H. Tamamura, N. Yoshida, M. Waki, A. Matsumoto, O. Yoshie, A small molecule CXCR4 inhibitor that blocks T cell line-tropic HIV-1 infection, J. Exp. Med. 186 (1997) 1389-1393.
19. R. Arakaki, H. Tamamura, M. Premanathan, K. Kanbara, S. Ramanan, K. Mochizuki, M. Baba, N. Fujii, H. Nakashima, T134, a small-molecule CXCR4 inhibitor, has no cross-drug resistance with AMD3100, a CXCR4 antagonist with a different structure, J. Virol. 73 (1999) 1719-1723.
20. H. Tamamura, Y. Xu, T. Hattori, X. Zhang, R. Arakaki, K. Kanbara, A. Omagari, A. Otaka, T. Ibuka, N. Yamamoto, H. Nakashima, N. Fujii, A low-molecularweight inhibitor against the chemokine receptor CXCR4: a strong anti-HIV peptide T140, Biochem, Biophys. Res. Commun. 253 (1998) 877-882.
21. H. Tamamura, H. Tsutsumi, H. Masuno, S. Mizokami, K. Hiramatsu, Z. Wang, J.O. Trent, H. Nakashima, N. Yamamoto, S.C. Peiper, N. Fujii, Development of a linear type of low molecular weight CXCR4 antagonists based on T140 analogs, Org. Biomol. Chem. 4 (2006) 2354-2357.
22. W. Rozenbaum, D. Dormont, B. Spire, E. Vilmer, M. Gentilini, C. Griscelli, L. Montagnier, F. Barre-Sinoussi, J. Chermann, Antimoniotungstate (HPA 23) treatment of three patients with AIDS and one with prodrome, J. Lancet 325 (1985) 450-451.
23. E. De Clercq, Antiviral metal complexes, Met. Based Drugs 4 (1997) 173-192.
24. E. De Clercq, The bicyclam AMD3100 story, Nat. Rev. Drug Discov. 2 (2003) 581-587.
25. E. De Clercq, N. Yamamoto, R. Pauwels, J. Balzarini, M. Witvrouw, K. De Vreese, Z. Debyser, B. Rosenwirth, P. Peichl, R. Datema, Highly potent and selective inhibition of human immunodeficiency virus by the bicyclam derivative JM3100, Antimicrob. Agents Chemother. 38 (1994) 668-674.
26. K. De Vreese, D. Reymen, P. Griffin, A. Steinkasserer, G. Werner, G.J. Bridger, J. Este, W. James, G.W. Henson, J. Desmyter, J. Anne, I. De Clercq, The bicyclams, a new class of potent human immunodeficiency virus inhibitors, block viral entry after binding, Antivir. Res. 29 (1996) 209-219.
27. K. De Vreese, I. Van Nerum, K. Vermeire, J. Anne, E. De Clercq, Sensitivity of human immunodeficiency virus to bicyclam derivatives is influenced by the three-dimensional structure of gp120, Antimicrob. Agents Chemother. 41 (1997) 2616-2620.
28. D. Schols, J.A. Este, G. Henson, E. De Clercq, Bicyclams, a class of potent anti-HIV agents, are targeted at the HIV coreceptor fusin/CXCR-4, Antivir. Res. 35 (1997) 147-156.
29. S. Hatse, K. Princen, G. Bridger, E. De Clercq, D. Schols, Chemokine receptor inhibition by AMD3100 is strictly confined to CXCR4, FEBS Lett. 527 (2002) 255-262.
30. C.W. Hendrix, A.C. Collier, M.M. Lederman, D. Schols, R.B. Pollard, S. Brown, J.B. Jackson, R.W. Coombs, M.J. Glesby, C.W. Flexner, G.J. Bridger, K. Badel, R.T. MacFarland, G.W. Henson, G. Calandra, Safety, pharmacokinetics, and antiviral activity of AMD3100, a selective CXCR4 receptor inhibitor, in HIV-1 infection, J. Acquir. Immune Defic. Syndr. 37 (2004) (1999) 1253-1262.
31. E. De Clercq, The AMD3100 story: the path to the discovery of a stem cell mobilizer (Mozobil), Biochem. Pharmacol. 77 (2009) 1655-1664.
32. G.J. Bridger, R.T. Skerlj, S. Padmanabhan, S.A. Martellucci, G.W. Henson, S. Struyf, M. Witvrouw, D. Schols, E. De Clercq, Synthesis and structureactivity relationships of phenylenebis(methylene)-linked bis-azamacrocycles that inhibit HIV-1 and HIV-2 replication by antagonism of the chemokine receptor CXCR4, J. Med. Chem. 42 (1999) 3971-3981.
33. J. Dessolin, P. Galea, P. Vlieghe, J.C. Chermann, J.L. Kraus, New bicyclam-AZT conjugates: design, synthesis, anti-HIV evaluation, and their interaction with CXCR-4 coreceptor, J. Med. Chem. 42 (1999) 229-241.
34. K. Princen, S. Hatse, K. Vermeire, S. Aquaro, E. De Clercq, L.O. Gerlach, M. Rosenkilde, T.W. Schwartz, R. Skerlj, G. Bridger, D. Schols, Inhibition of human immunodeficiency virus replication by a dual CCR5/CXCR4 antagonist, J. Virol. 78 (2004) 12996-13006.
35. G.J. Bridger, R.T. Skerlj, P.E. Hernandez-Abad, D.E. Bogucki, Z. Wang, Y. Zhou, S. Nan, E.M. Boehringer, T. Wilson, J. Crawford, M. Metz, S. Hatse, K. Princen, E. De Clercq, D. Schols, Synthesis and structure-activity relationships of azamacrocyclic C-X-C chemokine receptor 4 antagonists: analogues containing a single azamacrocyclic ring are potent inhibitors of T-cell tropic (X4) HIV-1 replication, J. Med. Chem. 53 (2010) 1250-1260.
36. L.O. Gerlach, J.S. Jakobsen, K.P. Jensen, M.R. Rosenkilde, R.T. Skerlj, U. Ryde, G.J. Bridger, T.W. Schwartz, Metal ion enhanced binding of AMD3100 to Asp262 in the CXCR4 receptor, Biochemistry 42 (2003) 710-717.
37. S. Hatse, K. Princen, E. De Clercq, M.M. Rosenkilde, T.W. Schwartz, P.E. Hernandez-Abad, R.T. Skerlj, G.J. Bridger, D. Schols, AMD3465, a monomacrocyclic CXCR4 antagonist and potent HIV entry inhibitor, Biochem. Pharmacol. 70 (2005) 752-761.
38. V. Bodart, V. Anastassov, M.C. Darkes, S.R. Idzan, J. Labrecque, G. Lau, R.M. Mosi, K.S. Neff, K.L. Nelson, M.C. Ruzek, K. Patel, Z. Santucci, R. Scarborough, R.S. Wong, G.J. Bridger, R.T. Macfarland, S.P. Fricker, Pharmacology of AMD3465: a small molecule antagonist of the chemokine receptor CXCR4, Biochem. Pharmacol. 78 (2009) 993-1000.
39. D. Schols, S. Claes, S. Hatse, K. Princen, K. Vermeire, E. De Clercq, R. Skerlj, G. Bridger, G. Calandra, Anti-HIV Activity Profile of AMD070, an Orally Bioavailable CXCR4 Antagonist, 2003. Abstract book.
40. R.T. Skerlj, G.J. Bridger, A. Kaller, E.J. McEachern, J.B. Crawford, Y. Zhou, B. Atsma, J. Langille, S. Nan, D. Veale, T. Wilson, C. Harwig, S. Hatse, K. Princen, E. De Clercq, D. Schols, Discovery of novel small molecule orally bioavailable C-X-C chemokine receptor 4 antagonists that are potent inhibitors of T-tropic (X4) HIV-1 replication, J. Med. Chem. 53 (2010) 3376-3388.
41. N.D. Stone, S.B. Dunaway, C. Flexner, C. Tierney, G.B. Calandra, S. Becker, Y.J. Cao, I.P. Wiggins, J. Conley, R.T. MacFarland, J.G. Park, C. Lalama, S. Snyder, B. Kallungal, K.L. Klingman, C.W. Hendrix, Multiple-dose escalation study of the safety, pharmacokinetics, and biologic activity of oral AMD070, a selective CXCR4 receptor inhibitor, in human subjects, Antimicrob. Agents Chemother. 51 (2007) 2351-2358.
42. R. Skerlj, G. Bridger, E. McEachern, C. Harwig, C. Smith, T. Wilson, D. Veale, H. Yee, J. Crawford, K. Skupinska, R. Wauthy, W. Yang, Y. Zhu, D. Bogucki, M. Di Fluri, J. Langille, D. Huskens, E. De Clercq, D. Schols, Synthesis and SAR of novel CXCR4 antagonists that are potent inhibitors of T tropic (X4) HIV-1 replication, Bioorg. Med. Chem. Lett. 21 (2011) 262-266.
43. R. Skerlj, G. Bridger, E. McEachern, C. Harwig, C. Smith, A. Kaller, D. Veale, H. Yee, K. Skupinska, R. Wauthy, L. Wang, I. Baird, Y. Zhu, K. Burrage, W. Yang, M. Sartori, D. Huskens, E. De Clercq, D. Schols, Design of novel CXCR4 antagonists that are potent inhibitors of T-tropic (X4) HIV-1 replication, Bioorg. Med. Chem. Lett. 21 (2011) 1414-1418.
44. K.S. Gudmundsson, P.R. Sebahar, L.D. Richardson, J.F. Miller, E.M. Turner, J.G. Catalano, A. Spaltenstein, W. Lawrence, M. Thomson, S. Jenkinson, Amine substituted N-(1H-benzimidazol-2ylmethyl)-5,6,7,8-tetrahydro-8-quinolinamines as CXCR4 antagonists with potent activity against HIV-1, Bioorg. Med. Chem. Lett. 19 (2009) 5048-5052.
45. J.F. Miller, E.M. Turner, K.S. Gudmundsson, S. Jenkinson, A. Spaltenstein, M. Thomson, P. Wheelan, Novel N-substituted benzimidazole CXCR4 antagonists as potential anti-HIV agents, Bioorg. Med. Chem. Lett. 20 (2010) 2125-2128.
46. K.S. Gudmundsson, S.D. Boggs, J.G. Catalano, A. Svolto, A. Spaltenstein, M. Thomson, P. Wheelan, S. Jenkinson, Imidazopyridine-5,6,7,8-tetrahydro-8-quinolinamine derivatives with potent activity against HIV-1, Bioorg. Med. Chem. Lett. 19 (2009) 6399-6403.
47. S.D. Boggs, K. Gudmundsson, Chemical Compounds, 2007. US2007254910.
48. S. Jenkinson, M. Thomson, D. McCoy, M. Edelstein, S. Danehower, W. Lawrence, P. Wheelan, A. Spaltenstein, K. Gudmundsson, Blockade of X4-tropic HIV-1 cellular entry by GSK812397, a potent noncompetitive CXCR4 receptor antagonist, Antimicrob. Agents Chemother. 54 (2010) 817-824.
49. J.F. Miller, K.S. Gudmundsson, L. D'Aurora Richardson, S. Jenkinson, A. Spaltenstein, M. Thomson, P. Wheelan, Synthesis and SAR of novel isoquinoline CXCR4 antagonists with potent anti-HIV activity, Bioorg. Med. Chem. Lett. 20 (2010) 3026-3030.
50. V.M. Truax, H. Zhao, B.M. Katzman, A.R. Prosser, A.A. Alcaraz, M.T. Saindane, R.B. Howard, D. Culver, R.F. Arrendale, P.R. Gruddanti, T.J. Evers, M.G. Natchus, J.P. Snyder, D.C. Liotta, L.J. Wilson, Discovery of tetrahydroisoquinoline-based CXCR4 antagonists, ACS Med. Chem. Lett. 4 (2013) 1025-1030.
51. J.G. Catalano, K.S. Gudmundsson, A. Svolto, S.D. Boggs, J.F. Miller, A. Spaltenstein, M. Thomson, P. Wheelan, D.J. Minick, D.P. Phelps, S. Jenkinson, Synthesis of a novel tricyclic 1,2,3,4,4a,5,6,10b-octahydro-1,10-phenanthroline ring system and CXCR4 antagonists with potent activity against HIV-1, Bioorg. Med. Chem. Lett. 20 (2010) 2186-2190.
52. H. Zhao, A.R. Prosser, D.C. Liotta, L.J. Wilson, Discovery of novel N-aryl piperazine CXCR4 antagonists, Bioorg. Med. Chem. Lett. 25 (21) (2015) 4950-4955.
53. G. Thoma, M.B. Streiff, J. Kovarik, F. Glickman, T. Wagner, C. Beerli, H.G. Zerwes, Orally bioavailable isothioureas block function of the chemokine receptor CXCR4 in vitro and in vivo, J. Med. Chem. 51 (2008) 7915-7920.
54. L. Wang, C. Cherian, S.K. Desmoulin, L. Polin, Y. Deng, J. Wu, Z. Hou, K. White, J. Kushner, L.H. Matherly, A. Gangjee, Synthesis and antitumor activity of a novel series of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitors of purine biosynthesis with selectivity for high affinity folate receptors and the proton-coupled folate transporter over the reduced folate carrier for cellular entry, J. Med. Chem. 53 (2010) 1306-1318.
55. K. Ichiyama, S. Yokoyama-Kumakura, Y. Tanaka, R. Tanaka, K. Hirose, K. Bannai, T. Edamatsu, M. Yanaka, Y. Niitani, N. Miyano-Kurosaki, H. Takaku, Y. Koyanagi, N. Yamamoto, A duodenally absorbable CXC chemokine receptor 4 antagonist, KRH-1636, exhibits a potent and selective anti-HIV-1 activity, Proc. Natl. Acad. Sci. U. S. A. 100 (2003) 4185-4190.
56. C.A. Mosley, L.J. Wilson, J.M. Wiseman, J.W. Skudlarek, D.C. Liotta, Recent patents regarding the discovery of small molecule CXCR4 antagonists, Expert Opin. Ther. Pat. 19 (2009) 23-38.
57. T. Yamazaki, H. Maruoka, S. Suzuki, T. Mukade, K. Hirose, M. Yanaka, N. Yamamoto, Nitrogenous Compounds and Antiviral Drugs Containing the Same, 2004. US2004092556.
58. T. Yamazaki, A. Saitou, M. Ono, S. Yokoyama, K. Bannai, K. Hirose, M. Yanaka, Novel Nitrogenous Compound and Use Thereof, 2004. US20040254221.
59. T. Murakami, S. Kumakura, T. Yamazaki, R. Tanaka, M. Hamatake, K. Okuma, W. Huang, J. Toma, J. Komano, M. Yanaka, Y. Tanaka, N. Yamamoto, The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100, Antimicrob. Agents Chemother. 53 (2009) 2940-2948.
60. S. Hatse, K. Princen, L.O. Gerlach, G. Bridger, G. Henson, E. De Clercq, T.W. Schwartz, D. Schols, Mutation of Asp(171) and Asp(262) of the chemokine receptor CXCR4 impairs its coreceptor function for human immunodeficiency virus-1 entry and abrogates the antagonistic activity of AMD3100, Mol. Pharmacol. 60 (2001) 164-173.
61. T. Nakasone, S. Kumakura, M. Yamamoto, T. Murakami, N. Yamamoto, Single oral administration of the novel CXCR4 antagonist, KRH-3955, induces an efficient and long-lasting increase of white blood cell count in normal macaques, and prevents CD4 depletion in SHIV-infected macaques: a preliminary study, Med. Microbiol. Immunol. 202 (2013) 175-182.
62. M. Kokubo, Y. Takaoka, S. Shibayama, Compound Containing Basic Group and Use Thereof, 2008. US2008009495.
63. C.H. Wu, C.P. Chang, J.S. Song, J.J. Jan, M.C. Chou, S.H. Wu, K.C. Yeh, Y.C. Wong, C.J. Hsieh, C.T. Chen, T.T. Kao, S.Y. Wu, C.F. Yeh, C.T. Tseng, Y.S. Chao, K.S. Shia, Discovery of novel stem cell mobilizers that target the CXCR4 receptor, ChemMedChem 7 (2012) 209-212.
64. C.H. Wu, C.J. Wang, C.P. Chang, Y.C. Cheng, J.S. Song, J.J. Jan, M.C. Chou, Y.Y. Ke, J. Ma, Y.C. Wong, T.C. Hsieh, Y.C. Tien, E.A. Gullen, C.F. Lo, C.Y. Cheng, Y.W. Liu, A.A. Sadani, C.H. Tsai, H.P. Hsieh, L.K. Tsou, K.S. Shia, Function-oriented development of CXCR4 antagonists as selective human immunodeficiency virus (HIV)-1 entry inhibitors, J. Med. Chem. 58 (2015) 1452-1465.
65. B.D. Cox, A.R. Prosser, Y. Sun, Z. Li, S. Lee, M.B. Huang, V.C. Bond, J.P. Snyder, M. Krystal, L.J. Wilson, D.C. Liotta, Pyrazolo-piperidines exhibit dual inhibition of CCR5/CXCR4 HIV entry and reverse transcriptase, ACS Med. Chem. Lett. 6 (2015) 753-757.
66. D. Das, K. Maeda, Y. Hayashi, N. Gavande, D.V. Desai, S.B. Chang, A.K. Ghosh, H. Mitsuya, Insights into the mechanism of inhibition of CXCR4: identification of Piperidinylethanamine analogs as anti-HIV-1 inhibitors, Antimicrob. Agents Chemother. 59 (2015) 1895-1904.
67. S. Ueda, M. Kato, S. Inuki, H. Ohno, B. Evans, Z.X. Wang, S.C. Peiper, K. Izumi, E. Kodama, M. Matsuoka, H. Nagasawa, S. Oishi, N. Fujii, Identification of novel non-peptide CXCR4 antagonists by ligand-based design approach, Bioorg. Med. Chem. Lett. 18 (2008) 4124-4129.
68. W. Zhan, Z. Liang, A. Zhu, S. Kurtkaya, H. Shim, J.P. Snyder, D.C. Liotta, Discovery of small molecule CXCR4 antagonists, J. Med. Chem. 50 (2007) 5655-5664.
69. H. Tamamura, A. Ojida, T. Ogawa, H. Tsutsumi, H. Masuno, H. Nakashima, N. Yamamoto, I. Hamachi, N. Fujii, Identification of a new class of low molecular weight antagonists against the chemokine receptor CXCR4 having the dipicolylamine-zinc(II) complex structure, J. Med. Chem. 49 (2006) 3412-3415.