Inhibitors of the entry of HIV into host cells

Current Opinion in Drug Discovery and Development

Volumn 6, Issue 4, 2003, Pages 451-461

  Meanwell, Nicholas A ^a   Kadow, John F ^a  

^a BRISTOL MYERS SQUIBB PHARMACEUTICAL RESEARCH INSTITUTE   (United States)

Author keywords

CCR5 chemokine receptor antagonists; CD4; CXCR4 chemokine receptor antagonists; Enfuvirtide; gp120 inhibitors; gp41 inhibitors; HIV attachment; HIV entry; HIV fusion inhibitor; HIV membrane fusion

Indexed keywords

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 BENZOYL 1 [(4 METHOXY 1H PYRROLO[2,3 B]PYRIDIN 3 YL)OXOACETYL] 2 METHYLPIPERAZINE; AMD 3465; ANTIVIRUS AGENT; APLAVIROC; CD4 IMMUNOGLOBULIN G2; CHEMOKINE RECEPTOR CCR5; CHEMOKINE RECEPTOR CXCR4; E 913; ENFUVIRTIDE; FP 21399; G PROTEIN COUPLED RECEPTOR; 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; PIPERAZINE DERIVATIVE; PRO 140; PROTEIN INHIBITOR; RANTES; T 1249; TERPHENYL DERIVATIVE; UNCLASSIFIED DRUG; VICRIVIROC;

ANTIVIRAL ACTIVITY; CLINICAL TRIAL; DENDRITIC CELL; DRUG DESIGN; DRUG HALF LIFE; DRUG ISOLATION; DRUG RESEARCH; DRUG SENSITIVITY; DRUG TARGETING; DRUG TOLERABILITY; ELECTRON MICROSCOPY; HUMAN; IC 50; PHASE 1 CLINICAL TRIAL; REVIEW; STRUCTURE ACTIVITY RELATION; VIRUS ISOLATION; VIRUS LOAD; VIRUS STRAIN; X RAY CRYSTALLOGRAPHY;

ANTI-HIV AGENTS; DRUG DESIGN; HIV ENVELOPE PROTEIN GP120; HIV ENVELOPE PROTEIN GP41; HIV INFECTIONS; HUMANS; RECEPTORS, CCR5; RECEPTORS, CXCR4; RECEPTORS, HIV;

EID: 0041528454     PISSN: 13676733     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (99)

1. Richman DD: HIV chemotherapy. Nature (2001) 410(6831):995-1001.
2. Cohen OJ, Fauci AS: Current strategies in the treatment of HIV infection. Adv Intern Med (2001) 46:207-246.
3. Montaner LJ: Structured treatment interruptions to control HIV-1 and limit drug exposure. Trends Immunol (2001) 22(2):92-96.
4. Dybul M, Chun T-W, Yoder C, Hidalgo H, Belson M, Hertogs K, Larder B, Dewar RL, Fox CH, Hallahan CW, Justement JS et al: Short-cycle structured intermittent treatment of chronic HIV infection with highly active antiretroviral therapy: Effects on virologic, immunologic, and toxicity parameters. Proc Natl Acad Sci USA (2001) 98(26):15161-15166.
5. Oxenius A, Price DA, Günthard HF, Dawson SJ, Fagard C, Perrin L, Fischer M, Weber R, Plana M, Garcia F, Hirschel B et al: Stimulation of HIV-specific cellular immunity by structured treatment interruption fails to enhance viral control in chronic HIV infection. Proc Natl Acad Sci USA (2002) 99(21):13747-13752.
6. Gulick RM: Structured treatment interruption in patients infected with HIV: A new approach to therapy? Drugs (2002) 62(2):245-253.
7. Little SJ, Holte S, Routy J-P, Daar ES, Markowitz M, Collier AC, Koup RA, Mellors JW, Connick E, Conway B, Kilby M et al: Antiretroviral-drug resistance among patients recently infected with HIV. N Engl J Med (2002) 347(6):385-394.
8. De Clercq E: New anti-HIV agents and targets. Med Res Rev (2002) 22(6):531-565.
9. Miller MD, Hazuda DJ: New antiretroviral agents: Looking beyond protease and reverse transcriptase. Curr Opin Microbiol (2001) 4(5):535-539.
10. Young SD: Inhibition of HIV-1 integrase by small molecules: The potential for a new class of AIDS chemotherapeutics. Curr Opin Drug Discovery Dev (2001) 4(4):402-410.
11. Cooley LA, Lewin SR: HIV-1 cell entry and advances in viral entry inhibitor therapy. J Clin Virol (2003) 26(2):121-132.
12. Pierson TC, Doms RW: HIV-1 entry inhibitors: New targets, novel therapies. Immunol Lett (2003) 85(2):113-118.
13. O'Hara BM, Olson WC: HIV entry inhibitors in clinical development. Curr Opin Pharmacol (2002) 2(5):523-528.
14. Petrik J: Fusion inhibitors. IDrugs (2002) 5(1):77-83.
15. 2, a novel heterotetramer which neutralizes primary HIV-1 isolates. AIDS Res Hum Retroviruses (1995) 11(5):533-539.
16. 2 (PRO-542): Potential for cross-linking human immunodeficiency virus type 1 envelope spikes. J Virol (2001) 75(14):6682-6686.
17. Nagashima KA, Thompson DAD, Rosenfeld SI, Maddon PJ, Dragic T, Olson WC: Human immunodeficiency virus type 1 entry inhibitors PRO-542 and T-20 are potently synergistic in blocking virus-cell and cell-cell fusion. J Infect Dis (2001) 183(7):1121-1125.
18. Ketas TJ, Frank I, Klasse PJ, Sullivan BM, Gardner JP, Spenlehauer C, Nesin M, Olson WC, Moore JP, Pope M: Human immunodeficiency virus type 1 attachment, coreceptor, and fusion inhibitors are active against both direct and trans infection of primary cells. J Virol (2003) 77(4):2762-2767.
19. Johnson JM, Lowy I, Fletcher CV, O'Neill TJ, Tran DN, Ketas TJ, Trkola A, Klotman ME, Maddon PJ, Olson WC, Israel RJ: Single-dose safety, pharmacology, and antiviral activity of the human immunodeficiency virus (HIV) type 1 entry inhibitor PRO-542 in HIV-infected adults. J Infect Dis (2000) 182(1):326-329.
20. Olson WC, Israel RJ, Jacobson JM, Vassilatos L, Tran D, Stambler N, Barish M, O'Hara BM, Ketas TJ, Sullivan BM, Moore JP et al: Viral resistance and pharmacologic analyses of phase I/II study patients treated with the HIV-1 entry inhibitor PRO-542. 10th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA (2003):Abs 561.
21. Dezube BJ, Dahl TA, Wong TK, Chapman B, Ono M, Yamaguchi N, Gillies SD, Chen LB, Crumpacker CS: A fusion inhibitor (FP-21399) for the treatment of human immunodeficiency virus infection: A phase 1 study. J Infect Dis (2000) 182(2):607-610.
22. Lin P-F, Robinson B, Gong Y-F, Ricarrdi K, Guo Q, Deminie C, Rose R, Wang T, Meanwell N, Yang Z, Wang H et al: Identification and Characterization of a novel inhibitor of HIV-1 entry - I: Virology and resistance. 9th Conference on Retroviruses and Opportunistic Infections, Seattle, WA, USA (2002):Abs 9. The first description of an orally bioavailable and small, drug-like molecule that interferes with the CD4-gp120 interaction and is a potent antiviral agent in cell culture.
23. Lin P-F, Guo K, Fridell R, Ho H-T, Yamanaka G, Colonno RJ: Identification and characterization of a novel inhibitor of HIV-1 entry - II: Mechanism of action. 9th Conference on Retroviruses and Opportunistic Infections, Seattle, WA, USA (2002):Abs 10.
24. Wang T, Zhang Z, Wallace OB, Deshpande M, Fang H, Yang Z, Zadjura LM, Tweedie DL, Huang S, Zhao F, Ranadive S et al: The discovery of 4-benzoyl-1-[(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)oxoacetyl] -2-methyl-piperazine (BMS-377806) - a new inhibitor of HIV that interferes with the CD4-gp120 interaction. (2003) manuscript submitted.
25. Schwarz MK, Wells TNC: New therapeutics that modulate chemokine networks. Nat Rev Drug Disc (2002) 1(5):347-358.
26. Scozzafava A, Mastrolorenzo A, Supuran CT: Non-peptidic chemokine receptor antagonists as emerging anti-HIV agents. J Enzyme Inhib Med Chem (2002) 17(2):69-76.
27. Kazmierski W, Bifulco N, Yang H, Boone L, DeAnda F, Watson C, Kenakin T: Recent progress in discovery of small-molecule CCR5 chemokine receptor ligands as HIV-1 inhibitors. Bioorg Med Chem (2003) 11(13):2663-2676.
28. Paterlini MG: Structure modeling of the chemokine receptor CCR5: Implications for ligand binding and selectivity. Biophys J (2002) 83(6):3012-3031.
29. 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.
30. Baba M, Nishimura O, Kanzaki N, Okamoto M, Sawada H, Iizawa Y, Shiraishi M, Aramaki Y, Okonogi K, Ogawa Y, Meguro K et al: A small-molecule nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proc Natl Acad Sci USA (1999) 96(10):5698-5703. The first description of a potent CCR5 antagonist that demonstrates antiviral activity in cell culture.
31. Dragic T, Trkola A, Thompson DAD, Cormier EG, Kajumo FA, Maxwell E, Lin SW, Ying W, Smith SO, Sakmar TP, Moore JP: 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(10):5639-5644.
32. Shiraishi M, Aramaki Y, Seto M, Imoto H, Nishikawa Y, Kanzaki N, Okamoto M, Sawada H, Nishimura O, Baba M, Fujino M: 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(10):2049-2063.
33. Iizawa Y, Kanzaki N, Takashima K, Miyake H, Tagawa Y, Sugihara Y, Baba M: Anti-HIV-1 activity of TAK-220, a small molecule CCR5 antagonist. 10th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA (2003):Abs 11.
34. Reynes J, Rouzier R, Kanouni T, Baillat V, Baroudy B, Keung A, Hogan C, Markowitz M, Laughlin M: SCH C: Safety and antiviral effects of a CCR5 receptor antagonist in HIV-1-infected subjects. 9th Conference on Retroviruses and Opportunistic Infections, Seattle, WA, USA (2002):Abs 1. This clinical study represented the first description of a CCR5 antagonist demonstrating antiviral activity in HIV-infected patients.
35. Estes JA: Sch-351125 and Sch-350634 Schering-Plough. Curr Opin Invest Drugs (2002) 3(3):379-383.
36. McCombie SW, Tagat JR, Vice SF, Lin S-I, Steensma R, Palani A, Neustadt BR, Baroudy BM, Strizki JM, Endres M, Cox K 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(3):567-571.
37. Tsamis F, Gavrilov S, Kajumo F, Seibert C, Kuhmann S, Ketas T, Trkola A, Palani A, Clader JW, Tagat JR, McCombie S 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(9):5201-5208.
38. Tremblay CL, Giguel F, Kollmann C, Guan Y, Chou T-C, Baroudy BM, Hirsch MS: Anti-human immunodeficiency virus interactions of Sch-C (Sch 351125), a CCR5 antagonist, with other antiretroviral agents in vitro. Antimicrob Agents Chemother (2002) 46(5):1336-1339.
39. Trkola A, Kuhmann SE, Strizki JM, Maxwell E, Ketas T, Morgan T, Pugach P, Xu S, Wojcik L, Tagat J, Palani A 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(1):395-400.
40. Mosier DE, Picchio GR, Gulizia RJ, Sabbe R, Poignard P, Picard L, Offord RE, Thompson DA, Wilken J: 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(5):3544-3550.
41. Tagat J, McCombie S, Nazareno D, Steensma R, Labroli M, Baroudy B, Strizki J, Cox K: Discovery of potent, selective, and orally active CCR5 antagonists for the potential treatment of HIV Infection. 225th ACS National Meeting, New Orleans, LA, USA (2003):MEDI-015.
42. Chen Z, Hu B, Huang W, He T, Huang Y, Strizki J, Xu S, Wojcik L, Whitcomb JM, Zhang L et al: HIV-1 mutants less susceptible to Sch-D, a novel small molecule antagonist of CCR5. 10th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA (2003):Abs 396-T.
43. Maeda K, Yoshimura K, Shibayama S, Habashita H, Tada H, Sagawa K, Miyakawa T, Aoki M, Fukushima D, Mitsuya H: Novel low molecular weight spirodiketopiperazine derivatives potently inhibit R5 HIV-1 infection through their antagonistic effects on CCR5. J Biol Chem (2001) 276(37):35194-35200.
44. Maeda K, Nakata H, Miyakawa T, Ogata H, Koh Y, Shibayama S, Sagawa K, Takaoka Y, Moravek J, Koyanagi Y, Mitsuya H: AK-602: A novel HIV-specific spirodiketopiperazine CCR5 inhibitor potent against a wide spectrum of R5-HIV. 10th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA (2003):Abs 10.
45. Nakata H, Maeda K, Kawano Y, Miyakawa T, Shibayama S, Matsuo M, Takaoka Y, Koyanagi Y, Mitsuya H: Potent in vivo anti-R5-HIV effects of AK-602, a novel spirodiketopiperazine (SDP)-containing HIV-specific CCR5 inhibitor, in hu-PBMC-NOD-SCID mice. 10th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA (2003):Abs 564a.
46. Dorr P, Macartney M, Rickett G, Smith-Burchnell C, Dobbs S, Mori J, Griffin P, Lok J, Irvine R, Westby M, Hitchcock C et al: UK-427,857, a novel small molecule HIV entry inhibitor is a specific antagonist of the chemokine receptor CCR5. 10th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA (2003):Abs 12.
47. Napier C, Dorr P, Gladue R, Halliday R, Leishman D, Machin I, Mitchell R, Nedderman A, Perros M, Roffey S, Walker D et al: The preclinical pharmacokinetics and safety pharmacology of the anti-HIV CCR5 antagonist, UK-427,857. 10th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA (2003):Abs 546A.
48. Abel S, Van der Ryst E, Muirhead GJ, Rosario M, Edgington A, Weissgerber G: Pharmacokinetics of single and multiple oral doses of UK-427,857 - a novel CCR5 antagonist in healthy volunteers. 10th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA (2003):Abs 547.
49. Lynch CL, Willoughby CA, Hale JJ, Holson EJ, Budhu RJ, Gentry AL, Rosauer KG, Caldwell CG, Chen P, Mills SG, MacCoss M et al: 1,3, 4-Trisubstituted pyrrolidine CCR5 receptor antagonists: Modifications of the arylpropylpiperidine side chains. Bioorg Med Chem Left (2003) 13(1):119-123.
50. Willoughby CA, Rosauer KG, Hale JJ, Budhu RJ, Mills SG, Chapman KT, MacCoss M, Malkowitz L, Springer MS, Gould SL, DeMartino JA et al: 1,3,4 trisubstituted pyrrolidine CCR5 receptor antagonists bearing 4-aminoheterocycle substituted piperidine side chains. Bioorg Med Chem Left (2003) 13(3):427-431.
51. Hale JJ, Budhu RJ, Mills SG, MacCoss M, Gould SL, DeMartino JA, Springer MS, Siciliano SJ, Malkowitz L, Schleif WA, Hazuda D 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 Left (2002) 12(20):2997-3000.
52. Kumar S, Kwei GY, Poon GK, Iliff SA, Wang Y, Chen Q, Franklin RB, Didolkar V, Wang RW, Yamazaki M, Chiu S-H et al: Pharmacokinetics and interactions of a novel antagonist of chemokine receptor 5 (CCR5) with ritonavir in rats and monkeys: Role of CYP3A and P-glycoprotein. J Pharmacol Exp Ther (2003) 304(3):1161-1171.
53. Castonguay LA, Weng Y, Adolfsen W, Di Salvo J, Kilbum R, Caldwell CG, Daugherty BL, Finke PE, Hale JJ, Lynch CL 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(6):1544-1550.
54. Poli G: PRO-140 Progenics. IDrugs (2001) 4(9):1068-1071.
55. Trkola A, Ketas TJ, Nagashima KA, Zhao L, Cilliers T, Morris L, Moore JP, Maddon PJ, Olson WC: Potent, broad-spectrum inhibition of human immunodeficiency virus type 1 by the CCR5 monoclonal antibody PRO-140. J Virol (2001) 75(2):579-588.
56. Fujii N, Nakashima H, Tamamura H: The therapeutic potential of CXCR4 antagonists in the treatment of HIV. Expert Opin Investig Drugs (2003) 12(2):185-195.
57. DeClercq E: Inhibition of HIV infection by bicyclams, highly potent and specific CXCR4 antagonists. Mol Pharmacol (2000) 57(5):833-839.
58. Schols D, Claes S, DeClercq E, Hendrix C, Bridger G, Calandra G, Henson GW, Fransen S, Huang W, Whitcomb JM, Petropoulos CJ: AMD-3100, a CXCR4 antagonist, reduced HIV viral load and X4 virus levels in humans. 9th Conference on Retroviruses and Opportunistic Infections, Seattle, WA, USA (2002):Abs 2. This clinical study provides the first demonstration that a CXCR4 antagonist can reduce viral load in HIV-infected patients.
59. Hendrix C, Collier AC, Lederman M, Pollard R, Brown S, Glesby M, Flexner C, Bridger G, Badel K, MacFarland R et al: AMD-3100 CXCR4 receptor blocker fails to reduce HIV viral load by >1 log following 10-day continuous infusion. 9th Conference on Retroviruses and Opportunistic Infections, Seattle, WA, USA (2002):Abs 391-T.
60. Hatse S, Princen K, Bridger G, Skerlj R, Henson G, Clercq ED, Schols D: A specific CXCR4 antagonist with potent anti-HIV activity. 15th International Conference on Antiviral Research, Prague, Czech Republic (2002):Abs 5.
61. Schols D, Claes S, Hatse S, Princen K, Vermeire K, De Clercq E, Skerlj R, Bridger G, Calandra G: Anti-HIV activity profile of AMD-070, an orally bioavailable CXCR4 antagonist, 10th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA (2003):Abs 563.
62. Ichiyama K, Yokoyama-Kumakura S, Tanaka Y, Tanaka R, Hirose K, Bannai K, Edamatsu T, Yanaka M, Niitani Y, Miyano-Kuroaki N, Takaku H et al: A duodenally absorbable CXC chemokine recepetor 4 antagonist, KRH-1636, exhibits a potent and selective anti-HIV-1 activity. Proc Natl Acad Sci USA (2003) 100(7):4185-4190.
63. Sanders DA: Ancient viruses in the fight against HIV. Drug Disc Today (2003) 8(7):287-291.
64. Gallina A, Hanley TM, Mandel R, Trahey M, Broder CC, Viglianti GA, Ryser HJ-P: Inhibitors of protein-disulfide isomerase prevent cleavage of disulfide bonds in receptor-bound glycoprotein 120 and prevent HIV-1 entry. J Biol Chem (2002) 277(52):50579-50588.
65. Barbouche R, Miquelis R, Jones IM, Fenouillet E: Protein-disulfide isomerase-mediated reduction of two disulfide bonds of HIV envelope glycoprotein 120 occurs post-CXCR4 binding and is required for fusion. J Biol Chem (2003) 278(5):3131-3136.
66. Matthias LJ, Yam PTW, Jiang X-M, Vandegraaf N, Li P, Poumbourios P, Donoghue N, Hogg PJ: Disulfide exchange in domain 2 of CD4 is required for entry of HIV-1. Nat Immunol (2002) 3(8):727-732.
67. Ryser HJ, Levy EM, Mandel R, DiSciullo GJ: Inhibition of human immunodeficiency virus infection by agents that interfere with thioldisulfide interchange upon virus-receptor interaction. Proc Natl Acad Sci USA (1994) 91(10):4559-4563.
68. Fenouillet E, Barbouche R, Courageot J, Miquelis R: The catalytic activity of protein disulfide isomerase is involved in human immunodeficiency virus envelope-mediated membrane fusion after CD4 cell binding. J Infect Dis (2001) 183(5):744-752.
69. Chen RY, Kilby JM, Saag MS: Enfuvirtide. Expert Opin Investig Drugs (2002) 11(12):1837-1843.
70. Culleli-Young M, Lesson PA, del Fresno M, Bayés M: Enfuvirtide. Drugs Future (2002) 27:450-457.
71. LaBonte J, Lebbos J, Kirkpatrick P: Enfuvirtide. Nat Rev Drug Disc (2003) 2(5):345-346.
72. Reeves JD, Gallo SA, Ahmad N, Miamidian JL, Harvey PE, Sharron M, Pöhlmann S, Sfakianos JN, Derdeyn CA, Blumenthal R, Hunter E et al: Sensitivity of HIV-1 to entry inhibitors correlates with envelope/coreceptor affinity, receptor density, and fusion kinetics. Proc Natl Acad Sci USA (2002) 99(25):16249-16254.
73. Derdeyn CA, Decker JM, Sfakianos JN, Wu X, O'Brien WA, Ratner L, Kappes JC, Shaw GM, Hunter E: Sensitivity of human immunodeficiency virus type 1 to the fusion inhibitor T-20 is modulated by coreceptor specificity defined by the V3 loop of gp120. J Virol (2000) 74(18):8358-8367.
74. Labrosse B, Labemardière J-L, Dam E, trouplin V, Skrabal K, Clavel F, Mammano F: Baseline susceptibility of primary human immunodeficiency virus type 1 to entry inhibitors. J Virol (2003) 77(2):1610-1613.
75. Wei, X, Decker JM, Liu H, Zhang Z, Arani RB, Kilby JM, Saag MS, Wu X, Shaw GM, Kappes JC: Emergence of resistant human immunodeficiency virus type 1 in patients receiving fusion inhibitor (T-20) monotherapy. Antimicrob Agents Chemother (2002) 46(6):1896-1905.
76. Hanna SL, Yang C, Owen SM, Lal RB: Resistance mutation in HIV entry inhibitors. AIDS (2002) 16(12):1603-1608.
77. Whitcomb JM, Huang W, Fransen S, Wrin T, Paxinos E, Toma J, Greenberg M, Sista P, Melby T, Matthews T, DeMasi R et al: Analysis of baseline enfuvirtide (T-20) susceptibility and co-receptor tropism in two phase III study populations. 10th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA (2003):Abs 557.
78. Greenberg ML, Melby T, Sista P, DeMasi R, Cammack N, Salgo M, Whitcomb J, Petropoulos C, Matthews TJ: Baseline and on-treatment susceptibility to enfuvirtide seen in TORO 1 and TORO 2 to 24 weeks. 10th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA (2003):Abs 141.
79. Lalezari JP, Henry K, O'Heam M, Montaner JSG, Piliero PJ, Trottier B, Walmsley S, Cohen C, Kuritzkes DR, Eron JJ Jr, Chung J et al: Enfuvirtide, an HIV-1 fusion inhibitor for drug-resistant HIV infection in North and South America. N Engl J Med (2003) 348(22):2175-2185. This article describes one of the two clinical studies (see reference [80]) that provided the basis for regulatory approval of enfuvirtide.
80. Lazzarin A, Clotet B, Cooper D, Reynes J, Arasteh K, Nelson M, Katlama C, Stellbrink H-J, Delfraissy J-F, Lange J, Huson L et al: Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N Engl J Med (2003) 348(22):2186-2195. This article describes one of the two clinical studies (see reference [79]) that provided the basis for regulatory approval of enfuvirtide.
81. Jiang S, Zhao Q, Debnath AK: Peptide and non-peptide HIV fusion inhibitors. Curr Pharm Des (2002) 8(8):563-580.
82. Sia SK, Carr PA, Cochran AG, Malashkevich VN, Kim PS: Short constrained peptides that inhibit HIV-1 entry. Proc Natl Acad Sci USA (2002) 99(23):14664-14669.
83. Conway B: T-1249 Trimeris Inc. Curr Opin Anti-Infect Invest Drugs (2000) 2(3):317-322.
84. Gulick RM: New antiretroviral drugs. Clin Microbiol Infect (2003) 9(3):186-193.
85. Omer BP, Ernst JT, Hamilton AD: Toward proteomimetics: Terphenyl derivatives as structural and functional mimics of extended regions of an α-helix. J Am Chem Soc (2001) 123(22):5382-5383.
86. L antagonist based on α-helix mimicry. J Am Chem Soc (2002) 124(40):11838-11839.
87. Ernst JT, Kutzki O, Debnath AK, Jiang S, Lu H, Hamilton AD: Design of a protein surface antagonist based on α-helix mimicry: Inhibition of gp41 assembly and viral fusion. Angew Chem Int Ed (2002) 41(2):278-281.
88. TAKEDA CHEMICAL INDUSTRIES LTD (Shiraishi M, Baba M, Seto M, Aramaki Y, Kanzaki N, Miyamoto N, lizawa Y): Preparation of benzazepine derivatives as CCR5 antagonists. WO-00314110 (2003).
89. TAKEDA CHEMICAL INDUSTRIES LTD (Shiraishi M, Baba M, Aikawa K, Kanzaki N, Seto M, Iizawa Y): Preparation of 1-benzazocine-5-carboxamides and related bicyclic compounds as CCR-5 antagonists for use against HIV infectious and other diseases. WO-00314105 (2003).
90. PFIZER LTD (Perros M, Price DA, Stammen BLC, Wood A): Tropane derivatives useful in therapy. WO-00190106 (2001).
91. PFIZER INC (Armour DR, Price DA, Stammen BLC, Wood A, Perros M, Edwards MP): Piperidines as CCR5 modulators. WO-00039125 (2000).
92. PFIZER INC (Armour DR, Price DA, Stammen BLC, Wood A, Perros M, Edwards MP): Aminoazacycloalkanes as CCR5 modulators. EP-01013276 (2000).
93. PFIZER INC (Armour DR, Price DA, Stammen BLC, Wood A, Perros M, Edwards MP): Preparation of acylaminophenylpropylbenzimidazolylazabicycloalkanes and related compounds as CCR5 receptor modulators. WO-00038680 (2000).
94. ANORMED INC (Bridger GJ, Boehringer EM, Wang Z, Schols D, Skerlj RT, Bogucki DE): Chemokine receptor binding heterocyclic compounds, WO-00144229 (2001).
95. ANORMED INC (Bridger GJ, Boehringer EM, Wang Z, Schols D, Skerlj RT, Bogucki DE): Preparation of antiviral macrocyclic polyamines. (2003) US-06506770.
96. ANORMED INC (Bridger G, Skerlj R, Kaller A, Harwig C, Bogucki D, Wilson TR, Crawford J, McEachern EJ, Atsma B, Nan S, Zhou Y et al): Chemokine receptor binding heterocyclic compounds. WO-00222600 (2002).
97. ANORMED INC (Bridger G, Skerlj R, Kaller A, Harwig C, Bogucki D, Wilson TR, Crawford J, McEachem EJ, Atsma B, Nan S, Zhou Y et al): Chemokine receptor-binding heterocyclic compounds. WO-00222599 (2002).
98. ANORMED INC (Bridger G, Skerli R, Kaller A, Harwig C, Bogucki D, Wilson TR, Crawford J, McEachem EJ, Atsman B, Nan S, Zhou Y et al): Chemokine receptor binding heterocyclic compounds. WO-00234745 (2002).
99. KUREHA CHEMICAL INDUSTRY CO LTD (Yamazaki T, Saitou A, Ono M, Yokoyama S, Bannai K, Hirose K, Yanaka M): Preparation of amino acid amide derivatives as antagonists of chemokine CXCR4 receptor. WO-00329218 (2003).