Small-molecule antagonists of CCR5 and CXCR4: A promising new class of anti-HIV-1 drugs

Current Pharmaceutical Design

Volumn 10, Issue 17, 2004, Pages 2041-2062

  Seibert, Christoph ^a   Sakmar, Thomas P ^a  

^a ROCKEFELLER UNIVERSITY   (United States)

Author keywords

Antagonist; CCR5; Chemokine receptor; CXCR4; Entry inhibitor; GPCR; HIV 1

Indexed keywords

1 ACETYL N [3 [4 (4 CARBAMOYLBENZYL) 1 PIPERIDINYL]PROPYL] N (3 CHLORO 4 METHYLPHENYL) 4 PIPERIDINECARBOXAMIDE; 1,1' [1,4 PHENYLENEBIS(METHYLENE)]BIS(1,4,8,11 TETRAAZACYCLOTETRADECANE); 4 [(4 BROMOPHENYL)(ETHOXYIMINO)METHYL] 1' [(2,4 DIMETHYL 3 PYRIDINYL)CARBONYL] 4' METHYL 1,4' BIPIPERIDINE; 4 [1 [(2,4 DIMETHYL 3 PYRIDINYL)CARBONYL] 4 METHYL 4 PIPERIDINYL] 2 METHYL 1 [1 [4 (TRIFLUOOROMETHYL)PHENYL]ETHYL]PIPERAZINE; 4 BENZOYL 1 [(4 METHOXY 1H PYRROLO[2,3 B]PYRIDIN 3 YL)OXOACETYL] 2 METHYLPIPERAZINE; 4,4' [CARBONYLBIS[IMINO 1H PYRROLE 4,2 DIYLCARBONYLIMINO(1 METHYL 1H PYRROLE 4,2 DIYL)CARBONYLIMINO]]BIS(1,7 NAPHTHALENESULFONIC ACID); ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; ANTIVIRUS AGENT; APLAVIROC; CD4 ANTIGEN; CD4 IMMUNOGLOBULIN G2; CELL PROTEIN; CHEMOKINE RECEPTOR CCR5; CHEMOKINE RECEPTOR CXCR4; DISTAMYCIN A DERIVATIVE; ENFUVIRTIDE; G PROTEIN COUPLED RECEPTOR; GLYCOPROTEIN GP 120; KRH 1636; MARAVIROC; N [4 [[[6,7 DIHYDRO 2 (4 METHYLPHENYL) 5H BENZOCYCLOHEPTEN 8 YL]CARBONYL]AMINO]BENZYL] N,N DIMETHYL 2H TETRAHYDROPYRAN 4 AMINIUM CHLORIDE; PIPERIDINE DERIVATIVE; PRO 140; PROTEINASE INHIBITOR; PYRROLIDINE DERIVATIVE; RNA DIRECTED DNA POLYMERASE INHIBITOR; SCH 350654; T 1249; UNCLASSIFIED DRUG; UNINDEXED DRUG; VIRUS PROTEIN; VIRUS RECEPTOR;

ANTIBIOTIC RESISTANCE; CELL MEMBRANE; CLINICAL TRIAL; COMBINATION CHEMOTHERAPY; DRUG BIOAVAILABILITY; DRUG RECEPTOR BINDING; DRUG SCREENING; DRUG TARGETING; DRUG TOXICITY; ERADICATION THERAPY; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HOST CELL; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; LIFE CYCLE; MEDICAL DOCUMENTATION; MORBIDITY; MORTALITY; NONHUMAN; PRIORITY JOURNAL; PROTEIN FAMILY; PROTEIN PROTEIN INTERACTION; RAT; REVIEW; SCIENTIFIC LITERATURE; STRUCTURE ACTIVITY RELATION; VIRUS REPLICATION; VIRUS STRAIN;

ANIMALS; ANTI-HIV AGENTS; BINDING SITES; CLINICAL TRIALS, PHASE I; HIV-1; HUMANS; RECEPTORS, CCR5; RECEPTORS, CXCR4; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 3042595910     PISSN: 13816128     EISSN: None     Source Type: Journal    
DOI: 10.2174/1381612043384312     Document Type: Review

References (167)

1. Deeks SG, Smith M, Holodniy M, Kahn JO. HIV-1 protease inhibitors. A review for clinicians. JAMA 1997; 277: 145-53.
2. Balzarini J. Suppression of resistance to drugs targeted to human immunodeficiency virus reverse transcriptase by combination therapy. Biochem Pharmacol 1999; 58: 1-27.
3. Montaner JS, Montessori V, Harrigan R, O'Shaughnessy M, Hogg R. Antiretroviral therapy: 'the state of the art'. Biomed Pharmacother 1999; 53: 63-72.
4. Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998; 338: 853-60.
5. Richman DD. HIV chemotherapy. Nature 2001; 410: 995-1001.
6. Louie M, Markowitz M. Goals and milestones during treatment of HIV-1 infection with antiretroviral therapy: a pathogenesis-based perspective. Antiviral Res 2002; 55: 15-25.
7. Finzi D, Blankson J, Siliciano JD, Margolick JB, Chadwick K, Pierson T, et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med 1999; 5: 512-7.
8. Furtado MR, Callaway DS, Phair JP, Kunstman KJ, Stanton JL, Macken CA, et al. Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy. N Engl J Med 1999; 340: 1614-22.
9. Yerly S, Kaiser L, Race E, Bru JP, Clavel F, Perrin L. Transmission of antiretroviral-drug-resistant HIV-1 variants. Lancet 1999; 354: 729-33.
10. Michael NL, Moore JP. HIV-1 entry inhibitors: evading the issue. Nat Med 1999; 5: 740-2.
11. Moore JP, Stevenson M. New targets for inhibitors of HIV-1 replication. Nat Rev Mol Cell Biol 2000; 1: 40-9.
12. LaBranche CC, Galasso G, Moore JP, Bolognesi DP, Hirsch MS, Hammer SM. HIV fusion and its inhibition. Antiviral Res 2001; 50: 95-115.
13. De Clercq E. New developments in anti-HIV chemotherapy. Biochim Biophys Acta 2002; 1587: 258-75.
14. O'Hara BM, Olson WC. HIV entry inhibitors in clinical development. Curr Opm Pharmacol 2002; 2: 523-8.
15. Meanwell NA, Kadow JF. Inhibitors of the entry of HIV into host cells. Curr Opin Drug Discov Devel 2003; 6: 451-61.
16. Moore JP, Doms RW. The entry of entry inhibitors: a fusion of science and medicine. Proc Natl Acad Sci USA 2003; 100: 10598-602.
17. Berger EA, Murphy PM, Farber JM. Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu Rev Immunol 1999; 17:657-700.
18. Wild CT, Shugars DC, Greenwell TK, McDanal CB, Matthews TJ. Peptides corresponding to a predictive alpha-helical domain of human immunodeficiency virus type 1 gp41 are potent inhibitors of virus infection. Proc Natl Acad Sci USA 1994; 91: 9770-4.
19. Kilby JM, Hopkins S, Venetta TM, DiMassimo B, Cloud GA, Lee JY, et al. Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. Nat Med 1998; 4: 1302-7.
20. Trkola A, Pomales AB, Yuan H, Korber B, Maddon PJ, Allaway GP, et al. Cross-clade neutralization of primary isolates of human immunodeficiency virus type 1 by human monoclonal antibodies and tetrameric CD4-IgG. J Virol 1995; 69: 6609-17.
21. Lin PF, Blair W, Wang T, Spicer T, Guo Q, Zhou N, et al. A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding. Proc Natl Acad Sci USA 2003; 100: 11013-8.
22. Cammack N. Human immunodeficiency virus type 1 entry and chemokine receptors: a new therapeutic target. Antivir Chem Chemother 1999; 10: 53-62.
23. Schwarz M, Wells TN, Proudfoot AE. Chemokine receptors-the next therapeutic target for HIV? Receptors Channels 2001; 7: 417-28.
24. Kazmierski W, Bifulco N, Yang H, Boone L, DeAnda F, Watson C, et al. Recent Progress in Discovery of Small-Molecule CCR5 Chemokine Receptor Ligands as HIV-1 Inhibitors. Bioorg Med Chem 2003; 11: 2663-76.
25. Horuk R. Development and evaluation of pharmacological agents targeting chemokine receptors. Methods 2003; 29: 369-75.
26. Wise A, Gearing K, Rees S. Target validation of G-protein coupled receptors. Drug Discov Today 2002; 7: 235-46.
27. Zhang YJ, Moore JP. Will multiple coreceptors need to be targeted by inhibitors of human immunodeficiency virus type 1 entry? J Virol 1999; 73: 3443-8.
28. Zhang Y, Lou B, Lal RB, Gettie A, Marx PA, Moore JP. Use of inhibitors to evaluate coreceptor usage by simian and simian/human immunodeficiency viruses and human immunodeficiency virus type 2 in primary cells. J Virol 2000; 74: 6893-910.
29. de Roda Husman AM, Schuitemaker H. Chemokine receptors and the clinical course of HIV-1 infection. Trends Microbiol 1998; 6: 244-9.
30. Douek DC, Picker LJ, Koup RA. T cell dynamics in hiv-1 infection. Annu Rev Immunol 2003; 21: 265-304.
31. Liu R, Paxton WA, Choe S, Ceradini D, Martin SR, Horuk R, et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 1996; 86: 367-77.
32. Samson M, Libert F, Doranz BJ, Rucker J, Liesnard C, Farber CM, et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 1996; 382: 722-5.
33. Dean M, Carrington M, Winkler C, Huttley GA, Smith MW, Allikmets R, et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science 1996; 273: 1856-62.
34. Wu L, Paxton WA, Kassam N, Ruffing N, Rottman JB, Sullivan N, et al. CCR5 levels and expression pattern correlate with infectability by macrophage-tropic HIV-1, in vitro. J Exp Med 1997; 185: 1681-91.
35. O'Brien SJ, Moore JP. The effect of genetic variation in chemokines and their receptors on HIV transmission and progression to AIDS. Immunol Rev 2000; 177: 99-111.
36. Yang YF, Mukai T, Gao P, Yamaguchi N, Ono S, Iwaki H, et al. A non-peptide CCR5 antagonist inhibits collagen-induced arthritis by modulating T cell migration without affecting anti-collagen T cell responses. Eur J Immunol 2002; 32: 2124-32.
37. Gerard C, Rollins BJ. Chemokines and disease. Nat Immunol 2001; 2: 108-15.
38. Proudfoot AE. Chemokine receptors: multifaceted therapeutic targets. Nat Rev Immunol 2002; 2: 106-15.
39. Carter PH. Chemokine receptor antagonism as an approach to anti-inflammatory therapy: 'just right' or plain wrong? Curr Opin Chem Biol 2002; 6: 510-25.
40. Tachibana K, Hirota S, Iizasa H, Yoshida H, Kawabata K, Kataoka Y, et al. The chemokine receptor CXCR4 is essential for vascularization ofthe gastrointestinal tract. Nature 1998; 393: 591-4.
41. Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 1998; 393: 595-9.
42. Datema R, Rabin L, Hincenbergs M, Moreno MB, Warren S, Linquist V, et al. Antiviral efficacy in vivo of the anti-human immunodeficiency virus bicyclam SDZ SID 791 (JM 3100), an inhibitor of infectious cell entry. Antimicrob Agents Chemother 1996; 40: 750-4.
43. Hendrix CW, Flexner C, MacFarland RT, Giandomenico C, Fuchs EJ, Redpath E, et al. Pharmacokinetics and safety ofAMD-3100, a novel antagonist of the CXCR- 4 chemokine receptor, in human volunteers. Antimicrob Agents Chemother 2000; 44: 1667-73.
44. Schwarz MK, Wells TNC. New Therapeutics that Modulate Chemokine Networks. Nature Reviews Drug Discovery 2002; 1: 347-58.
45. Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, Lusso P. Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV- suppressive factors produced by CD8+ T cells. Science 1995; 270: 1811-5.
46. Bleul CC, Farzan M, Choe H, Parolin C, Clark-Lewis I, Sodroski J, et al. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature 1996; 382: 829-33.
47. Oberlin E, Amara A, Bachelerie F, Bessia C, Virelizier JL, Arenzana-Seisdedos F, et al. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature 1996; 382: 833-5.
48. Simmons G, Clapham PR, Picard L, Offord RE, Rosenkilde MM, Schwartz TW, et al. Potent inhibition of HIV-1 infectivity in macrophages and lymphocytes by a novel CCR5 antagonist. Science 1997; 276: 276-9.
49. Mosier DE, Picchio GR, Gulizia RJ, Sabbe R, Poignard P, Picard L, et al. Highly potent RANTES analogues either prevent CCR5-using human immunodeficiency virus type 1 infection in vivo or rapidly select for CXCR4-using variants. J Virol 1999; 73: 3544-50.
50. Townson JR, Graham GJ, Landau NR, Rasala B, Nibbs RJ. Aminooxypentane addition to the chemokine macrophage inflammatory protein-1alpha P increases receptor affinities and HIV inhibition. J Biol Chem 2000; 275: 39254-61.
51. Zaitseva M, Peden K, Golding H. HIV coreceptors: role of structure, posttranslational modifications, and internalization in viral-cell fusion and as targets for entry inhibitors. Biochim Biophys Acta 2003; 1614: 51-61.
52. Mack M, Luckow B, Nelson PJ, Cihak J, Simmons G, Clapham PR, et al. Aminooxypentane-RANTES induces CCR5 internalization but inhibits recycling: a novel inhibitory mechanism of HIV infectivity. J Exp Med 1998; 187: 1215-24.
53. Amara A, Gall SL, Schwartz O, Salamero J, Montes M, Loetscher P, et al. HIV coreceptor downregulation as antiviral principle: SDF-1alpha- dependent internalization of the chemokine receptor CXCR4 contributes to inhibition of HIV replication. J Exp Med 1997; 186: 139-46.
54. Olson WC, Rabut GE, Nagashima KA, Tran DN, Anselma DJ, Monard SP, et al. Differential inhibition of human immunodeficiency virus type 1 fusion, gp120 binding, and CC-chemokine activity by monoclonal antibodies to CCR5. J Virol 1999; 73: 4145-55.
55. Trkola A, Ketas TJ, Nagashima KA, Zhao L, Cilliers T, Morris L, et al. Potent, broad-spectrum inhibition of human immunodeficiency virus type 1 by the CCR5 monoclonal antibody PRO 140. J Virol 2001; 75: 579-88.
56. Scozzafava A, Mastrolorenzo A, Supuran CT. Non-peptidic chemokine receptors antagonists as emerging anti-HIV agents. J Enzyme Inhib Med Chem 2002; 17. 69-76.
57. Baba M, Nishimura O, Kanzaki N, Okamoto M, Sawada H, Iizawa Y, et al. A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proc Natl Acad Sci USA 1999; 96: 5698-703.
58. Shiraishi M, Aramaki Y, Seto M, Imoto H, Nishikawa Y, Kanzaki N, et al. Discovery of novel, potent, and selective small-molecule CCR5 antagonists as anti-HIV-1 agents: synthesis and biological evaluation of anilide derivatives with a quaternary ammonium moiety. J Med Chem 2000; 43: 2049-63.
59. Dragic T, Trkola A, Thompson DA, Cormier EG, Kajumo FA, Maxwell E, et al. A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5. Proc Natl Acad Sci USA 2000; 97: 5639-44.
60. Tagat JR, McCombie SW, Steensma RW, Lin S, Nazareno DV, Baroudy B, et al. Piperazine-Based CCR5 antagonists as HIV-1 inhibitors. I: 2(S)-methyl piperazine as a key pharmacophore element. Bioorg Med Chem Lett 2001; 11: 2143-6.
61. Tagat JR, Steensma RW, McCombie SW, Nazareno DV, Lin SI, Neustadt BR, et al. Piperazine-Based CCR5 Antagonists as HIV-1 Inhibitors. II. Discovery of 1-[2,4-Dimethyl-3-pyridinyl)carbonyl]- 4-methyl-4-[3(S)-methyl-4-[1(S)-[4-(trifluoro-methyl)phenyl]ethyl]- 1-piperazinyl]-piperidine N1-Oxide (Sch-350634), an Orally Bioavailable, Potent CCR5 Antagonist. J Med Chem 2001; 44: 3343-6.
62. Palani A, Shapiro S, Josien H, Bara T, Clader JW, Greenlee WJ, et al. Synthesis, SAR, and Biological Evaluation of Oximino-Piperidino- Piperidine Amides. 1. Orally Bioavailable CCR5 Receptor Antagonists with Potent Anti-HIV Activity. J Med Chem 2002; 45: 3143-60.
63. Boyle CD, Palani A. Structure-activity relationship studies: M2 and CCR5 receptor antagonists. Curr Top Med Chem 2003; 3: 1155-69.
64. Palani A, Shapiro S, Clader JW, Greenlee WJ, Cox K, Strizki J, et al. Discovery of 4-[(Z)-(4-Bromophenyl)- (ethoxyimino)methyl]-1′-[(2,4- dimethyl-3- pyridinyl)carbonyl]-4′-methyl-1,4′-bipiperidine N-Oxide (SCH 351125): An Orally Bioavailable Human CCR5 Antagonist for the Treatment of HIV Infection. J Med Chem 2001; 44: 3339-42.
65. McCombie SW, Tagat JR, Vice SF, Lin SI, Steensma R, Palani A, et al. Piperazine-based CCR5 antagonists as HIV-1 inhibitors. III: synthesis, antiviral and pharmacokinetic profiles of symmetrical heteroaryl carboxamides. Bioorg Med Chem Lett 2003; 13: 567-71.
66. Strizki JM, Xu S, Wagner NE, Wojcik L, Liu J, Hou Y, et al. SCH-C (SCH 351125), an orally bioavailable, small molecule antagonist of the chemokine receptor CCR5, is a potent inhibitor of HIV-1 infection in vitro and in vivo. Proc Natl Acad Sci USA 2001; 98: 12718-23.
67. Ketas TJ, Klasse PJ, Spenlehauer C, Nesin M, Frank I, Pope M, et al. Entry inhibitors SCH-C, RANTES, and T-20 block HIV type 1 replication in multiple cell types. AIDS Res Hum Retroviruses 2003; 19: 177-86.
68. Tremblay CL, Giguel F, Kollmann C, Guan Y, Chou TC, Baroudy BM, et al. Anti-Human Immunodeficiency Virus Interactions of SCH-C (SCH 351125), a CCR5 Antagonist, with Other Antiretroviral Agents In Vitro. Antimicrob Agents Chemother 2002; 46: 1336-9.
69. Palani A, Shapiro S, Clader JW, Greenlee WJ, Blythin D, Cox K, et al. Biological evaluation and interconversion studies of rotamers of SCH 351125, an orally bioavailable CCR5 antagonist. Bioorg Med Chem Lett 2003; 13: 705-8.
70. Palani A, Shapiro S, Clader JW, Greenlee WJ, Vice S, McCombie S, et al. Oximino-piperidino-piperidine-based CCR5 antagonists. Part 2: synthesis, SAR and biological evaluation of symmetrical heteroaryl carboxamides. Bioorg Med Chem Lett 2003; 13: 709-12.
71. Dorn CP, Finke PE, Oates B, Budhu RJ, Mills SG, MacCoss M, et al. Antagonists of the human CCR5 receptor as anti-HIV-1 agents. part 1: discovery and initial structure-activity relationships for 1-amino-2-phenyl-4-(piperidin-1-yl)butanes. Bioorg Med Chem Lett 2001; 11: 259-64.
72. Finke PE, Meurer LC, Oates B, Mills SG, MacCoss M, Malkowitz L, et al. Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 2: structure-activity relationships for substituted 2-Aryl-1-[N-(methyl)-N- (phenylsulfonyl)amino]-4-(piperidin-1-yl)butanes. Bioorg Med Chem Lett 2001; 11: 265-70.
73. Finke PE, Meurer LC, Oates B, Shah SK, Loebach JL, Mills SG, et al. Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 3: a proposed pharmacophore model for 1-[N-(methyl)-N-(phenylsuffonyl)amino]- 2-(phenyl)-4-[4-(substituted)piperidin-1-yl]butanes. Bioorg Med Chem Lett 2001; 11: 2469-73.
74. Finke PE, Oates B, Mills SG, MacCoss M, Malkowitz L, Springer MS, et al. Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 4: synthesis and structure-activity relationships for 1-[N-(methyl)-N- (phenylsulfonyl)amino]-2-(phenyl)-4-(4-(N-(alkyl)-N- (benzyloxycarbonyl)amino)piperidin-1-yl)butanes. Bioorg Med Chem Lett 2001; 11: 2475-9.
75. Kim D, Wang L, Caldwell CG, Chen P, Finke PE, Oates B, et al. Discovery of human CCR5 antagonists containing hydantoins for the treatment of HIV-1 infection. Bioorg Med Chem Lett 2001; 11: 3099-102.
76. Kim D, Wang L, Caldwell CG, Chen P, Finke PE, Oates B, et al. Design, synthesis, and SAR of heterocycle-containing antagonists of the human CCR5 receptor for the treatment of HIV-1 infection. Bioorg Med Chem Lett 2001 11: 3103-6.
77. Willoughby CA, Berk SC, kosauer KG, Degrado S, Chapman KT, Gould SL, et al. Combinatorial synthesis of CCR5 antagonists. Bioorg Med Chem Lett 2001; 11: 3137-41.
78. Hale JJ, Budhu RJ, Mills SG, MacCoss M, Malkowitz L, Siciliano S, et al. 1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 1: discovery of the pyrrolidine scaffold and determination of its stereochemical requirements. Bioorg Med Chem Lett 2001; 11: 1437-40.
79. Hale JJ, Budhu RJ, Holson EB, Finke PE, Oates B, Mills SG, et al. 1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists, Part 2: lead optimization affording selective, orally bioavailable compounds with potent anti-HIV activity. Bioorg Med Chem Lett 2001; 11: 2741-5.
80. Hale J, Budhu R, Mills S, MacCoss M, Gould S, DeMartino J, et al. 1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 3: polar functionality and its effect on anti-HIV-1 activity. Bioorg Med Chem Lett 2002; 12: 2997-3000.
81. Lynch C, Hale J, Budhu R, Gentry A, Mills S, Chapman K, et al. 1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 4: Synthesis of N-1 acidic functionality affording analogues with enhanced antiviral activity against HIV. Bioorg Med Chem Lett 2002; 12: 3001-4.
82. Willoughby CA, Rosauer KG, Hale JJ, Budhu RJ, Mills SG, Chapman KT, et al. 1,3,4 trisubstituted pyrrolidine CCR5 receptor antagonists bearing 4-aminoheterocycle substituted piperidine side chains. Bioorg Med Chem Lett 2003; 13: 427-31.
83. Lynch CL, Willoughby CA, Hale JJ, Holson EJ, Budhu RJ, Gentry AL, et al. 1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists: modifications of the arylpropylpiperidine side chains. Bioorg Med Chem Lett 2003; 13: 119-23.
84. Lynch CL, Hale JJ, Budhu RJ, Gentry AL, Finke PE, Caldwell CG, et al. CCR5 Antagonists: 3-(Pyrrolidin-1-yl)propionic Acid Analogues with Potent Anti-HIV Activity. Org Lett 2003; 5: 2473-5.
85. Castonguay LA, Weng Y, Adolfsen W, Di Salvo J, Kilburn R, Caldwell CG, et al. Binding of 2-Aryl-4-(piperidin-1-yl)butanamines and 1,3,4-Trisubstituted Pyrrolidines to Human CCR5: A Molecular Modeling-Guided Mutagenesis Study of the Binding Pocket. Biochemistry 2003; 42: 1544-50.
86. Lynch CL, Gentry AL, Hale JJ, Mills SG, MacCoss M, Malkowitz L, et al. CCR5 antagonists: bicyclic isoxazolidines as conformationally constrained N-1-substituted pyrrolidines. Bioorg Med Chem Lett 2002; 12: 677-9.
87. Veazey RS, Klasse PJ, Ketas TJ, Reeves JD, Piatak M Jr, Kunstman K, et al. Use of a small molecule CCR5 inhibitor in macaques to treat simian immunodeficiency virus infection or prevent simian-human immunodeficiency virus infection. J Exp Med 2003; 198: 1551-62.
88. Maeda K, Yoshimura K, Shibayama S, Habashita H, Tada H, Sagawa K, et al. Novel low molecular weight spirodiketopiperazine derivatives potently inhibit R5 HIV-1 infection through their antagonistic effects on CCR5. J Biol Chem 2001; 276: 35194-200.
89. Tsamis F, Gavrilov S, Kajumo F, Seibert C, Kuhmann S, Ketas T, et al. Analysis of the Mechanism by Which the Small-Molecule CCR5 Antagonists SCH-351125 and SCH-350581 Inhibit Human Immunodeficiency Virus Type 1 Entry. J Virol 2003; 77: 5201-8.
90. Seibert C, Ying W, Gavrilov S, Tsamis F, Kuhmann SE, Anandan P, et al. Interaction of small molecule inhibitors of HIV-1 entry with CCR5. Submitted for publication.
91. Billick E, Seibert C, Pugach P, Ketas T, Trkola A, Endres MJ, et al. A single amino acid explains the differential sensitivity of human and rhesus macaque CCR5 to small molecule inhibitors of human immunodeficiency virus type 1 entry and suggests a mechanism of action for these inhibitors. Submitted for publication.
92. Paterlini MG. Structure Modeling of the Chemokine Receptor CCR5: Implications for Ligand Binding and Selectivity. Biophys J 2002; 83: 3012-31.
93. Shieh T, Han M, Sakmar TP, Smith SO . The steric trigger in rhodopsin activation. J Mol Biol 1997; 269: 373-84.
94. Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, et al. Crystal structure of rhodopsin: A G protein-coupled receptor. Science 2000; 289: 739-45.
95. Rucker J, Samson M, Doranz BJ, Libert F, Berson JF, Yi Y, et al. Regions in beta-chemokine receptors CCR5 and CCR2b that determine HIV-1 cofactor specificity. Cell 1996; 87: 437-46.
96. Ross TM, Bieniasz PD, Cullen BR. Multiple residues contribute to the inability of murine CCR-5 to function as a coreceptor for macrophage-tropic human immunodeficiency virus type 1 isolates. J Virol 1998; 72: 1918-24.
97. Blanpain C, Doranz BJ, Vakili J, Rucker J, Govaerts C, Baik SS, et al. Multiple charged and aromatic residues in CCR5 amino-terminal domain are involved in high affinity binding of both chemokines and HIV-1 Env protein. J Biol Chem 1999; 274: 34719-27.
98. Howard OM, Shirakawa AK, Turpin JA, Maynard A, Tobin GJ, Carrington M, et al. Naturally occurring CCR5 extracellular and transmembrane domain variants affect HIV-1 Co-receptor and ligand binding function. J Biol Chem 1999; 274: 16228-34.
99. Dragic T, Trkola A, Lin SW, Nagashima KA, Kajumo F, Zhao L, et al. Amino-terminal substitutions in the CCR5 coreceptor impair gp120 binding and human immunodeficiency virus type 1 entry. J Virol 1998; 72: 279-85.
100. Rabut GF, Konner JA, Kajumo F, Moore JP, Dragic T. Alanine substitutions of polar and nonpolar residues in the amino- terminal domain of CCR5 differently impair entry of macrophage- and dualtropic isolates of human immunodeficiency virus type 1. J Virol 1998; 72: 3464-8.
101. Farzan M, Choe H, Vaca L, Martin K, Sun Y, Desjardins E, et al. A tyrosine-rich region in the N terminus of CCR5 is important for human immunodeficiency virus type 1 entry and mediates an association between gp120 and CCR5. J Virol 1998; 72: 1160-4.
102. Doranz BJ, Lu ZH, Rucker J, Zhang TY, Sharron M, Cen YH, et al. Two distinct CCR5 domains can mediate coreceptor usage by human immunodeficiency virus type 1. J Virol 1997; 71: 6305-14.
103. Dragic T. An overview of the determinants of CCR5 and CXCR4 co-receptor function. J Gen Virol 2001; 82: 1807-14.
104. Christopoulos A, Kenakin T. G protein-coupled receptor allosterism and complexing. Pharmacol Rev 2002; 54: 323-74.
105. Samson M, LaRosa G, Libert F, Paindavoine P, Detheux M, Vassart G, et al. The second extracellular loop of CCR5 is the major determinant of ligand specificity. J Biol Chem 1997; 272: 24934-41.
106. Blanpain C, Doranz BJ, Bondue A, Govaerts C, De Leener A, Vassart G, et al. The core domain of chemokines binds CCR5 extracellular domains while their amino terminus interacts with the transmembrane helix bundle. J Biol Chem 2003; 278: 5179-87.
107. Clanton DJ, Buckheit RW Jr, Terpening SJ, Kiser R, Mongelli N, Borgia AL, et al. Novel sulfonated and phosphonated analogs of distamycin which inhibit the replication of HIV. Antiviral Res 1995; 27: 335-54.
108. Howard OM, Korte T, Tarasova NI, Grimm M, Turpin JA, Rice WG, et al. Small molecule inhibitor of HIV-1 cell fusion blocks chemokine receptor-mediated function. J Leukoc Biol 1998; 64: 6-13.
109. Howard OM, Oppenheim JJ, Hollingshead MG, Covey JM, Bigelow J, McCormack JJ, et al. Inh ibition of in vitro and in vivo HIV replication by a distamycin analogue that interferes with chemokine receptor function: a candidate for chemotherapeutic and microbicidal application. J Med Chem 1998; 41: 2184-93.
110. Keith DE, Murray SR, Zaki PA, Chu PC, Lissin DV, Kang L, et al. Morphine activates opioid receptors without causing their rapid internalization. J Biol Chem 1996; 271: 19021-4.
111. Roettger BF, Ghanekar D, Rao R, Toledo C, Yingling J, Pinon D, et al. Antagonist-stimulated internalization of the G protein-coupled cholecystokinin receptor. Mol Pharmacol 1997; 51: 357-62.
112. Kazmierski WM, Boone L, Lawrence W, Watson C, Kenakin T. CCR5 chemokine receptors: gatekeepers of HIV-1 infection. Curr Drug Targets Infect Disord 2002; 2: 265-78.
113. Este JA, Cabrera C, Blanco J, Gutierrez A, Bridger G, Henson G, et al. Shift of clinical human immunodeficiency virus type 1 isolates from X4 to R5 and prevention of emergence of the syncytium-inducing phenotype by blockade of CXCR4. J Virol 1999; 73: 5577-85.
114. D'Aquila RT, Hughes M, Johnson VA. HIV-1 entry inhibitors and virus emergence. Nat Med 1999; 5: 1091.
115. Farber JM, Berger EA. HIV's response to a CCR5 inhibitor: I'd rather tighten than switch! Proc Natl Acad Sci USA 2002; 99: 1749-51.
116. Matthys P, Hatse S, Vermeire K, Wuyts A, Bridger G, Henson GW, et al. AMD3100, a potent and specific antagonist of the stromal cell-derived factor-1 chemokine receptor CXCR4, inhibits autoimmune joint inflarrunation in IFN-gamma receptor-deficient mice. J Immunol 2001; 167: 4686-92.
117. Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001; 410: 50-6.
118. Scotton CJ, Wilson JL, Milliken D, Stamp G, Balkwill FR. Epithelial cancer cell migration: a role for chemokine receptors? Cancer Res 2001; 61: 4961-5.
119. Scotton CJ, Wilson JL, Scott K, Stamp G, Wilbanks GD, Fricker S, et al. Multiple actions of the chemokine CXCL12 on epithelial tumor cells in human ovarian cancer. Cancer Res 2002; 62: 5930-8.
120. Rubin JB, Kung AL, Klein RS, Chan JA, Sun Y, Schmidt K, et al. A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Proc Natl Acad Sci USA 2003; 100: 13513-18.
121. Murphy PM, Baggiolini M, Charo IF, Hebert CA, Horuk R, Matsushima K, et al. International union of pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol Rev 2000; 52: 145-76.
122. Nagasawa T, Hirota S, Tachibana K, Takakura N, Nishikawa S, Kitamura Y, et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 1996; 382: 635-8.
123. Doranz BJ, Grovit-Ferbas K, Sharron MP, Mao SH, Goetz MB, Daar ES, et al. A small-molecule inhibitor directed against the chemokine receptor CXCR4 prevents its use as an HIV-1 coreceptor. J Exp Med 1997; 186: 1395-400.
124. Murakami T, Nakajima T, Koyanagi Y, Tachibana K, Fujii N, Tamamura H, et al. A small molecule CXCR4 inhibitor that blocks T cell line-tropic HIV-1 infection. J Exp Med 1997; 186: 1389-93.
125. Arakaki R, Tamamura H, Premanathan M, Kanbara K, Ramanan S, Mochizuki K, et al. T134, a small-molecule CXCR4 inhibitor, has no cross-drug resistance with AMD3100, a CXCR4 antagonist with a different structure. J Virol 1999; 73: 1719-23.
126. Tamamura H, Xu Y, Hattori T, Zhang X, Arakaki R, Kanbara K, et al. A low-molecular-weight inhibitor against the chemokine receptor CXCR4: a strong anti-HIV peptide T140. Biochem Biophys Res Commun 1998; 253: 877-82.
127. De Clercq E. Inhibition of HIV infection by bicyclams, highly potent and specific CXCR4 antagonists. Mol Pharmacol 2000; 57: 833-9.
128. De Clercq E, Yamamoto N, Pauwels R, Baba M, Schols D, Nakashima H, et al. 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 USA 1992; 89: 5286-90.
129. De Clercq E, Yamamoto N, Pauwels R, Balzarini J, Witvrouw M, De Vreese K, et al. Highly potent and selective inhibition of human immunodeficiency virus by the bicyclam derivative JM3100. Antimicrob Agents Chemother 1994; 38: 668-74.
130. Bridger GJ, Skerlj RT, Thornton D, Padmanabhan S, Martellucci SA, Henson GW, et al. Synthesis and structure-activity relationships of phenylenebis(methylene)-linked bis-tetraazamacrocycles that inhibit HIV replication. Effects of macrocyclic ring size and substituents on the aromatic linker. J Med Chem 1995; 38: 366-78.
131. Joao HC, De Vreese K, Pauwels R, De Clercq E, Henson GW, Bridger GJ. Quantitative structural activity relationship study of bis-tetraazacyclic compounds. A novel series of HIV-1 and HIV-2 inhibitors. J Med Chem 1995; 38: 3865-73.
132. Bridger GJ, Skerlj RT, Padmanabhan S, Martellucci SA, Henson GW, Abrams MJ, et al. Synthesis and structure-activity relationships of phenylenebis(methylene)-linked bis-tetraazamacrocycles that inhibit human immunodeficiency virus replication. 2. Effect of heteroaromatic linkers on the activity of bicyclams. J Med Chem 1996; 39: 109-19.
133. De Clercq E, Schols D. Inhibition of HIV infection by CXCR4 and CCR5 chemokine receptor antagonists. Antivir Chem Chemother 2001; 12 Suppl 1: 19-31.
134. Schols D, Struyf S, Van Damme J, Este JA, Henson G, De Clercq E. Inhibition of T-tropic HIV strains by selective antagonization of the chemokine receptor CXCR4. J Exp Med 1997; 186: 1383-8.
135. Schols D, Este JA, Henson G, De Clercq E. Bicyclams, a class of potent anti-HIV agents, are targeted at the IIIV coreceptor fusin/CXCR-4. Antiviral Res 1997; 35: 147-56.
136. Donzella GA, Schols D, Lin SW, Este JA, Nagashima KA, Maddon PJ, et al. AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co- receptor. Nat Med 1998; 4: 72-7.
137. Este JA, Cabrera C, De Clercq E, Struyf S, Van Damme J, Bridger G, et al. Activity of different bicyclam derivatives against human immunodeficiency virus depends on their interaction with the CXCR4 chemokine receptor. Mol Pharmacol 1999; 55: 67-73.
138. Bridger GJ, Skerlj RT, Padmanabhan S, Martellucci SA, Henson GW, Struyf S, et al. Synthesis and structure-activity 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 1999; 42: 3971-81.
139. Labrosse B, Brelot A, Heveker N, Sol N, Schols D, De Clercq E, et al. Determinants for sensitivity of human immunodeficiency virus coreceptor CXCR4 to the bicyclam AMD3100. J Virol 1998; 72: 6381-8.
140. Gerlach LO, Skerlj RT, Bridger GJ, Schwartz TW. Molecular interactions of cyclam and bicyclam non-peptide antagonists with the CXCR4 chemokine receptor. J Biol Chem 2001; 276: 14153-60.
141. Zhang WB, Navenot JM, Haribabu B, Tamamura H, Hiramatu K, Omagari A, et al. A point mutation that confers constitutive activity to CXCR4 reveals that T140 is an inverse agonist and that AMD3100 and ALX40-4C are weak partial agonists. J Biol Chem 2002; 277: 24515-21.
142. Endres MJ, Clapham PR, Marsh M, Ahuja M, Turner JD, McKnight A, et al. CD4-independent infection by HIV-2 is mediated by fusin/CXCR4. Cell 1996; 87: 745-56.
143. Brelot A, Heveker N, Pleskoff O, Sol N, Alizon M. Role of the first and third extracellular domains of CXCR-4 in human immunodeficiency virus coreceptor activity. J Virol 1997; 71: 4744-51.
144. Liles WC, Broxmeyer HE, Rodger E, Wood B, Hubel K, Cooper S, et al. Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist. Blood 2003; 102: 2728-30.
145. Hatse S, Princen K, Gerlach LO, Bridger G, Henson G, De Clercq E, et al. 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 2001; 60: 164-73.
146. Adam KR, Antolovich M, Atkinson IM, Leong AJ, Lindoy LF, McCool BJ, et al. On the Nature of the Host-Guest Interaction Between Cyclant and 4-tert-Butylbenzoic Acid - a System Pre-assembled for Metal Complex Formation. J. Chem. Soc., Chem. Commun. 1994; 13: 1539-40.
147. Gerlach LO, Jakobsen JS, Jensen KP, Rosenkilde MR, Skerlj RT, Ryde U, et al. Metal ion enhanced binding of AMD3100 to Asp262 in the CXCR4 receptor. Biochemistry 2003; 42: 710-7.
148. Trent JO, Wang ZX, Murray JL, Shao W, Tamamura H, Fujii N, et al. Lipid bilayer simulations of CXCR4 with inverse agonists and weak partial agonists. J Biol Chem 2003; 278: 47136-44.
149. Rosenkilde MM, Gerlach LO, Jacobsen JS, Skerlj RT, Bridger GJ, Schwartz TW. Molecular mechanism of AMD3100 antagonism in the CXCR4 receptor - transfer of binding site to the CXCR3 receptor. J Biol Chem 2004; 279: 3033-41.
150. Brelot A, Heveker N, Montes M, Alizon M. Identification of residues ofm CXCR4 critical for human immunodeficiency virus coreceptor and chemokine receptor activities. J Biol Chem 2000; 275: 23736-44.
151. Hatse S, Princen K, Vermeire K, Gerlach LO, Rosenkilde MM, Schwartz TW, et al. Mutations at the CXCR4 interaction sites for AMD3100 influence anti-CXCR4 antibody binding and HIV-1 entry. FEBS Lett 2003; 546: 300-6.
152. Kajumo F, Thompson DA, Guo Y, Dragic T. Entry of R5X4 and X4 human immunodeficiency virus type 1 strains is mediated by negatively charged and tyrosine residues in the amino- terminal domain and the second extracellular loop of CXCR4. Virology 2000; 271: 240-7.
153. Ichiyama K, Yokoyama-Kumakura S, Tanaka Y, Tanaka R, Hirose K, Bannai K, et al. A duodenally absorbable CXC chemokine receptor 4 antagonist, KRH-1636, exhibits a potent and selective anti-HIV-1 activity. Proc Natl Acad Sci USA 2003; 100: 4185-90.
154. Moulard M, Lortat-Jacob H, Mondor I, Roca G, Wyatt R, Sodroski J, et al. Selective interactions of polyanions with basic surfaces on human immunodeficiency virus type 1 gp120. J Virol 2000; 74: 1948-60.
155. Perrin L, Telenti A. HIV treatment failure: testing for HIV resistance in clinical practice. Science 1998; 280: 1871-3.
156. Domingo E, Menendez-Arias L, Quinones-Mateu ME, Holguin A, Gutierrez-Rivas M, Martinez MA, et al. Viral quasispecies and the problem of vaccine-escape and drug-resistant mutants. Prog Drug Res 1997; 48: 99-128.
157. Trkola A, Kuhmann SE, Strizki JM, Maxwell E, Ketas T, Morgan T, et al. HIV-1 escape from a small molecule, CCR5-specific entry inhibitor does not involve CXCR4 use. Proc Natl Acad Sci USA 2002; 99: 395-400.
158. Maeda Y, Foda M, Matsushita S, Harada S. Involvement of both the V2 and V3 regions of the CCR5-tropic human immunodeficiency virus type 1 envelope in reduced sensitivity to macrophage inflammatory protein 1alpha. J Virol 2000; 74: 1787-93.
159. Schols D, Este JA, Cabrera C, De Clercq E. T-cell-line-tropic human immunodeficiency virus type 1 that is made resistant to stromal cell-derived factor 1alpha contains mutations in the envelope gp120 but does not show a switch in coreceptor use. J Virol 1998; 72: 4032-7.
160. de Vreese K, Kofler-Mongold V, Leutgeb C, Weber V, Vermeire K, Schacht S, et al. The molecular target of bicyclams, potent inhibitors of human immunodeficiency virus replication. J Virol 1996; 70: 689-96.
161. Cheng-Mayer C, Shioda T, Levy JA. Host range, replicative, and cytopathic properties of human immunodeficiency virus type 1 are determined by very few amino acid changes in tat and gp120. J Virol 1991; 65: 6931-41.
162. Fouchier RA, Groenink M, Kootstra NA, Tersmette M, Huisman HG, Miedema F, et al. Phenotype-associated sequence variation in the third variable domain of the human immunodeficiency virus type 1 gp120 molecule. J Virol 1992; 66: 3183-7.
163. Kuhmann SE, Pugach P, Kunstman KJ, Taylor J, Stanfield RL, Snyder A, et al. Genetic and Phenotypic Analysis of Human Immunodeficiency Virus Type 1 Escape from a Small Molecule CCR5 Inhibitor. Submitted for publication.
164. De Vreese K, Van Nerum I, Veimeire K, Anne J, De Clercq E. Sensitivity of human immunodeficiency virus to bicyclam derivatives is influenced by the three-dimensional structure of gp120. Antimicrob Agents Chemother 1997; 41: 2616-20.
165. Huang L, Zhang L, Chen CH. Potential drug targets on the HIV-1 envelope glycoproteins, gp120 and gp41. Curr Pharm Design 2003; 9(18): 1453-62.
166. Moro S, Jacobson KA. Molecular modeling as a tool to investigate molecular recognition in P2Y receptors. Curr Pharm Design 2002; 8(26): 2401-13.
167. Saeki T, Naya A. CCR1 chemokine receptor antagonist. Curr Pharm Design 2003; 9(15): 1201-8.