New first and second generation inhibitors of human immunodeficiency virus-1 integrase

Expert Opinion on Therapeutic Patents

Volumn 21, Issue 8, 2011, Pages 1173-1189

  Pendri, Annapurna ^a   Meanwell, Nicholas A ^a   Peese, Kevin M ^a   Walker, Michael A ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

3 processing; AIDS; antiviral; elvitegravir; HIV; integration; LEDGF p75; lens epithelial derived growth factor; raltegravir; strand transfer; viral resistance

Indexed keywords

ELVITEGRAVIR; INTEGRASE INHIBITOR; MK 2048; RALTEGRAVIR; S GSK 1349572; UNCLASSIFIED DRUG;

CHEMICAL MODIFICATION; DRUG RESEARCH; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1 INFECTION; NONHUMAN; PATENT; REVIEW; VIRUS RESISTANCE;

ANIMALS; DRUG RESISTANCE, VIRAL; HIV INFECTIONS; HIV INTEGRASE; HIV INTEGRASE INHIBITORS; HIV-1; HUMANS; PATENTS AS TOPIC; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 79960690132     PISSN: 13543776     EISSN: 17447674     Source Type: Journal    
DOI: 10.1517/13543776.2011.586631     Document Type: Review

References (103)

1. LaFemina RL, Schneider CL, Robbins HL, et al. Requirement of active human immunodeficiency virus type 1 integrase enzyme for productive infection of human T-lymphoid cells. J Virol 1992;21:7414-19
2. Hazuda DJ, Felock P, Witmer M, et al. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 2000;287:646-50 (Pubitemid 30070911)
3. DeJesus E, Berger D, Markowitz M, et al. Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients. J Acquir Immune Defic Syndr 2006;43:1-5 (Pubitemid 44306480)
4. Markowitz M, Morales-Ramirez JO, Nguyen BY, et al. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-nave HIV-1-infected individuals. J Acquir Immune Defic Syndr 2006;43:509-15 (Pubitemid 44885615)
5. Thompson MA, Aberg JA, Cahn P, et al. International AIDS Society-USA. Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel. JAMA 2010;304:321-33
6. Zolopa AR. The evolution of HIV treatment guidelines: Current state-ofthe- art of ART. Antiviral Res 2010;85:241-4
7. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. 10 January 2011. p. 1-166. Available from: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. [Last accessed 24 January 2011]
8. Shimura K, Kodama EN. Elvitegravir: a new HIV integrase inhibitor. Antivir Chem Chemother 2009;20:79-85
9. Ramanathan S, Shen G, Hinkle J, et al. Pharmacokinetics of coadministered ritonavir-boosted elvitegravir and zidovudine, didanosine, stavudine, or abacavir. J Acquir Immune Defic Syndr 2007;46:160-6 (Pubitemid 47485733)
10. Ramanathan S, Shen G, Cheng A, Kearney BP. Pharmacokinetics of emtricitabine, tenofovir, and GS-9137 following coadministration of emtricitabine/tenofovir disoproxil fumarate and ritonavir-boosted GS-9137. J Acquir Immune Defic Syndr 2007;45:274-9 (Pubitemid 47012373)
11. Elion R, Gathe J, Rashbaum B, et al. The single-tablet regimen elvitegravir/ cobicistat/emtricitabine/tenofovirdisoproxil fumarate (EVG/COBI/FTC/TDF; QUAD) maintains a high rate of virologic suppression, and cobicistat (COBI) is an effective pharmacoenhancer through 48 weeks. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy; 12 - 15 September 2010; Boston, MA
12. Cohen C, Shamblaw D, Ruane P, et al. Single-tablet, fixed-dose regimen of elvitegravir/emtricitabine/tenofovir disoproxil fumarate/GS-9350 achieves a high rate of virologic suppression and GS-9350 is an effective booster. 17th Conference on Retroviruses and Opportunistic Infections; 16 - 19 February 2010; San Francisco, CA
13. Sato M, Motomura T, Aramaki H, et al. Novel HIV-1 integrase inhibitors derived from quinolone antibiotics. J Med Chem 2006;49:1506-8 (Pubitemid 43376497)
14. Summa V, Petrocchi A, Bonelli F, et al. Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection. J Med Chem 2008;51:5843-55
15. Hare S, Gupta SS, Valkov E, et al. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature 2010;464:232-6
16. Hare S, Vos AM, Clayton RF, et al. Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance. Proc Natl Acad Sci USA 2010;107:20057-62
17. Espeseth AS, Felock P, Wolfe A, et al. HIV-1 integrase inhibitors that compete with the target DNA substrate define a unique strand transfer conformation for integrase. Proc Natl Acad Sci USA 2000;97:11244-9
18. Cooper DA, Steigbigel RT, Gatell JM, et al. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med 2008;359:355-65
19. McColl DJ, Fransen S, Gupta S, et al. Resistance and cross-resistance to first generation integrase inhibitors: insights from a Phase II study of elvitegravir (GS- 9137). Antiviral Ther 2007;12:S11
20. Wai J, Fisher T, Embrey M, et al. Next generation of inhibitors of HIV-1 integrase strand transfer inhibitor: structural diversity and resistance profiles, The 14th Conference on Retroviruses and Opportunistic Infections; 25 - 28 February 2007; Los Angeles, CA
21. Underwood M, Johns B, Sato A, et al. S/GSK1349572: A next generation integrase inhibitor with activity against integrase inhibitor-resistant clinical isolates from patients experiencing virologic failure while on raltegravir therapy 5th International Aids Society Conference on HIV Pathogenesis, Treatment and Prevention; 19 - 22 July 2009; Capetown, South Africa
22. Sato A, Kobayashi M, Yoshinaga T, et al. S/GSK1349572 is a potent next generation HIV integrase inhibitor, 5th International Aids Society Conference on HIV Pathogenesis, Treatment and Prevention; 19 - 22 July 2009; Capetown, South Africa
23. Arribas J, Lazzarin A, Raffi F, et al. Once-daily S/GSK1349572 as part of combination therapy in antiretroviral naïve adults: rapid and potent antiviral responses in the interim 16-week analysis from SPRING-1 (ING112276). XVIII International AIDS Conference; 18 - 23 July 2010; Vienna, Austria
24. Eron J, Durant J, Poizot-Martin I, et al. Activity of a next generation integrase inhibitor (INI), S/GSK1349572, in subjects with HIV exhibiting raltegravirresistance: initial results of VIKING study (ING112961). XVIII International AIDS Conference; 18 - 23 July 2010; Vienna, Austria
25. Eron J, Livrozet JM, Morlat P, et al. Activity of Integrase Inhibitor, S/ GSK1349572 in Subjects with HIV Exhibiting Raltegravir Resistance: Week 24 Results of VIKING Study (ING112961). 10th International Congress on Drug Therapy in HIV Infection; 7 - 11 November 2010; Glasgow, Scotland
26. Walker MA. New approaches for inhibiting HIV integrase: a journey beyond the active site. Curr Opin Investig Drugs 2009;10:129-36
27. Voet ARD, De Maeyer M, Debyser Z, Christ F. In search of second-generation HIV integrase inhibitors: targeting integration beyond strand transfer. Future Med Chem 2009;1:1259-74
28. Busschots K, De Rijck J, Christ F, Debyser Z. In search of small molecules blocking interactions between HIV proteins and intracellular cofactors. Mol Biosyst 2009;5:21-31
29. Zhan P, Liu X, De Clercq E. Blocking nuclear import of pre-integration complex: an emerging anti-HIV-1 drug discovery paradigm. Curr Med Chem 2010;17(6):495-503
30. Wielens J, Headey SJ, Jeevarajah D, et al. Crystal structure of the HIV-1 integrase core domain in complex with sucrose reveals details of an allosteric inhibitory binding site. FEBS Lett 2010;584:1455-62
31. Al-Mawsawi LQ, Neamati N. Allosteric inhibitor development targeting HIV-1 integrase. ChemMedChem 2011;6:228-41
32. Johns BA, Svolto AC. Advances in two-metal chelation inhibitors of HIV integrase. Exp Opin Ther Patents 2008;18:1225-37
33. National Institutes of Health, Office of Technology Transfer WO2009026248; 2009
34. Zhao XZ, Semenova EA, Vu BC, et al. 2,3-Dihydro-6,7-dihydroxy-1H- isoindol- 1-one-based HIV-1 integrase inhibitors. J Med Chem 2008;51:251-9
35. Zhao XZ, Maddali K, Vu BC, et al. Examination of halogen substituent effects on HIV-1 integrase inhibitors derived from 2,3-dihydro-6,7-dihydroxy- 1H-isoindol-1-ones and 4,5-dihydroxy- 1H-isoindole-1,3(2H)-diones. Bioorg Med Chem Lett 2009;19:2714-17
36. Irm LLC. Terephthalamate compounds and compositions, and their use as HIV integrase inhibitors. WO2008073138; 2007
37. Bristol-Myers Squibb Co. HIV Integrase Inhibitors. WO2008154246; 2008
38. Merck & Co., Inc. HIV Integrase inhibitors. WO2010042391; 2010
39. Merck & Co., Inc. HIV Integrase inhibitors. WO2010042392; 2010
40. Merck & Co., Inc. Bridged compounds as HIV integrase inhibitors. WO2010088167; 2010
41. Bristol-Myers Squibb Co. Bridged heterocycles as HIV integrase inhibitors. WO2009117540; 2009
42. Merck & Co. Bridged compounds as HIV integrase inhibitors. WO2010088167; 2010
43. Avexa Ltd. Bicyclic pyrimidones and uses thereof. WO2008077188; 2008
44. Avexa Ltd. Thiazolopyrimidinones and uses thereof. WO2010000030; 2008
45. Avexa Ltd. Imidazopyrimidinones and uses thereof. WO2010000031; 2010
46. Avexa Ltd. Compounds having antiviral properties. WO2010000032; 2010
47. Jones ED, Vandegraff N, Le G, et al. Design of a series of bicyclic HIV-1 integrase inhibitors. Part 1: Selection of the scaffold. Bioorg Med Chem Lett 2010;20:5913-17
48. Le G, Vandegraff N, Rhodes DI, et al. Design of a series of bicyclic HIV-1 integrase inhibitors. Part 2: Azoles: effective metal chelators. Bioorg Med Chem Lett 2010;20:5909-12
49. Le G, Vandegraaff N, Rhodes DI, et al. Discovery of potent HIV integrase inhibitors active against raltegravir resistant viruses. Bioorg Med Chem Lett 2010;20:5013-18
50. Merck & Co., Inc. HIV Integrase inhibitors. WO2008048538; 2008
51. Merck & Co., Inc. HIV Integrase inhibitors. WO2009154870; 2009
52. Vandekerckhove L. GSK-1349572, a novel integrase inhibitor for the treatment of HIV infection. Curr Opin Investig Drugs 2010;11:203-12
53. Min S, Song SI, Borland J, et al. Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers. Antimicrob Agents Chemother 2009;54:254-8
54. Song SS, Min J, Borland Y, et al. The effect of lopinavir/ritonavir and darunavir/ritonavir on the HIV integrase inhibitor S/GSK1349572 in healthy participants. J Clin Pharm 2011;51:237
55. Yoshinaga T, Kanamori-Koyama M, Seki T, et al. Strong inhibition of wild-type and integrase inhibitor (INI)-resistant HIV integrase (IN) strand transfer reaction by the novel INI S/GSK1349572. International Drug Resistance Workshop; 8 - 12 June 2010; Dubrovnik, Croatia
56. Hightower KE, Wang R, Underwood MR. S/GSK1349572 demonstrates significantly slower dissociation rates than raltegravir when comparing wild-type and raltegravir-resistant integrase protein. International Drug Resistance Workshop; 8 - 12 June 2010; Dubrovnik, Croatia
57. Deanda FG, Hattori K, Yoshinaga T, et al. Structural models of HIV-1 integrase and DNA in complex with S/GSK1349572, raltegravir or elvitegravir: Structure-based rationale for INI resistance profiles. International Drug Resistance Workshop; 8 - 12 June 2010; Dubrovnik, Croatia
58. Kobayashi M, Yoshinaga T, Seki T, et al. Resistance associated mutations to dolutegravir (S/GSK1349572) in HIV-infected patients - Impact of HIV subtypes and prior raltegravir experience Antimicrob Agents Chemother 2011;55:813-21
59. GlaxoSmithKline LLC, Shionogi & Co. Ltd. Processes and intermediates for fused tricyclic carbamoylpyridone HIV integrase inhibitors. WO2010068262; 2010
60. Shionogi & Co. Ltd. GlaxoSmithKline LLC. Synthesis of fused tricyclic carbamoylpyridone HIV integraseinhibitors and intermediates. WO2010068253; 2010
61. Smithkline Beecham Corp. USA. Tricyclic heterocyclic compounds as antiviral agents and their preparation and use in the treatment of HIV infection. WO2010011812; 2010
62. Smithkline Beecham Corp. USA. Tricyclic heterocyclic compounds as antiviral agents and their preparation and use in the treatment of HIV infection. WO2010011819; 2010
63. Smithkline Beecham Corp. USA. Tricyclic heterocyclic compounds as antiviral agents and their preparation and use in the treatment of HIV infection. WO2010011814; 2010
64. Smithkline Beecham Corp. USA. Tricyclic heterocyclic compounds as antiviral agents and their preparation and use in the treatment of HIV infection. WO2010011815; 2010
65. Smithkline Beecham Corp. USA. Tetracyclic heterocyclic compounds as antiviral agents of HIV and their preparation useful in the treatment infection. WO2010011818; 2010
66. Smithkline Beecham Corp. USA. Prodrugs of HIV integrase inhibitors for the treatment of HIV infection, AIDS and AIDS-related complex. WO2010011816; 2010
67. Gilead Sciences, Inc. Integrase Inhibitors. WO2009067541; 2009
68. Gilead Sciences, Inc. Antiviral Compounds. WO2010011959; 2010
69. Gilead Sciences, Inc. Modulators of Pharmacokinetic Properties of Therapeutics. WO2008010921; 2008
70. Gilead Sciences, Inc. Modulators of Pharmacokinetic Properties of Therapeutics. WO2008103949; 2008
71. Gilead Sciences, Inc. Process and Intermediates for Preparing Integrase Inhibitors. WO2008033836; 2008
72. Ardea Biosciences, Inc. Novel compositions and methods of use. WO2009089263; 2009
73. Nagasawa JY, Song J, Chen H, et al. 6-Benzylamino 4-oxo-1,4-dihydro- 1,8-naphthyridines and 4-oxo- 1,4-dihydroquinolines as HIV integrase inhibitors. Bioorg Med Chem Lett 2011;21:760-6
74. Cherepanov P, Maertens G, Proost P, et al. HIV-1 Integrase forms stable tetramers and associates with LEDGF/ p75 protein in human cells. J Biol Chem 2003;278:372-81 (Pubitemid 36043586)
75. Maertens G, Cherepanov P, Pluymers W, et al. LEDGF /p75 is essential for nuclear and chromosomal targeting of HIV-1 integrase in human cells. J Biol Chem 2003;278:33528-39 (Pubitemid 37055807)
76. Ciuffi A, Llano M, Poeschla E, et al. A role for LEDGF /p75 in targeting HIV DNA integration. Nature Medicine 2005;11:1287-9 (Pubitemid 41752906)
77. Llano M, Saenz DT, Meehan A, et al. An Essential role for LEDGF /p75 in HIV Integration. Science 2006;314:461-4 (Pubitemid 44628966)
78. Christ F, Voet A, Marchand A, et al. Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication. Nat Chem Biol 2010;6:442-8
79. Katholieke Universiteit Leuven, Pepscan Therapeutics BV. HIV integrase helix 3-derived peptides blocking LEDGF/ p75 and integrase interaction and their therapeutic use as the inhibitors of lentiviral replication. WO2009095500; 2009
80. Yissum Research Development Co. of the Hebrew University of Jerusalem, Israel; Ramot At Tel-Aviv University Ltd. LEDGF/p75 integrase -binding domain peptides and therapeutic use for inhibiting HIV-1 replication and integrase activity. WO2008053478; 2008
81. Boehringer Ingelheim International G.m. b.H. Quinolines and related compounds as inhibitors of human immunodeficiency virus replication and their preparation and use in the treatment of HIV infection. WO2007131350; 2007
82. Boehringer Ingelheim International G.m. b.H. Preparation of 2-(quinolin-2-yl) acetic acid derivatives as inhibitors of human immunodeficiency virus replication. WO2009062289; 2009
83. Boehringer Ingelheim International G.m. b.H. Preparation of 2-(tert-butyloxy)-2- (2-methylquinolin-3-yl)acetic acid derivatives as inhibitors of human immunodeficiency virus replication. WO2009062285; 2009
84. Boehringer Ingelheim International G.m. b.H. Preparation of thieno[2,3-b]pyridine and thieno[3,2-b]pyridine derivatives as inhibitors of human immunodeficiency virus replication. WO2009062288; 2009
85. Boehringer Ingelheim International G.m. b.H. Preparation of pyrazolo[3,4-b] pyridine compounds as inhibitors of human immunodeficiency virus replication. WO2009062308; 2009
86. Katholieke Universiteit Leuven. Thieno [2,3-B] pyridine derivatives as viral replication inhbitors WO2010130842; 2010
87. Centre National De La Recherche Scientifique (CNRS). WO009845269; 1998
88. Mekouar K, Mouscadet JF, Desmaeele D, et al. Styrylquinoline derivatives: a new class of potent HIV-1 integrase inhibitors that block HIV-1 replication in CEM cells. J Med Chem 1998;41:2846-57 (Pubitemid 28350349)
89. Bioalliance Pharma Fr. Styrylquinolines, their process of preparation and their therapeutic uses WO2010010147; 2010
90. Deprez E, Barbe S, Kolaski M, et al. Mechanism of HIV-1 integrase inhibition by styrylquinoline derivatives in vitro. Mol Pharm 2004;65:85-98 (Pubitemid 38113889)
91. Mousnier A, Leh H, Mouscadet JF, Dargemont C. Nuclear import of HIV-1 integrase is inhibited in vitro by styrylquinoline derivatives. Mol Pharm 2004;66:783-8 (Pubitemid 39319449)
92. Bioalliance Pharma Fr. Quinoline derivative, synthesis method and medicines containing said derivatives. WO2003031413; 2003
93. Benard C, Zouhiri F, Normand-Bayle M, et al. Linker-modified quinoline derivatives targeting HIV-1 integrase: synthesis and biological activity. Bioorg Med Chem Lett 2004;14:2473-6 (Pubitemid 38515687)
94. Bioalliance Pharma Fr. Styrylquinolines, their process of preparation and their therapeutic uses. WO2010010148; 2010
95. Bioalliance Pharma Fr. Styrylquinolines, their process of preparation and their therapeutic uses. WO2010010148; 2010
96. Pharmacor, Inc. Pyridoxal-5-phospahte derivatives as HIV integrase inhibitors. WO2003082881; 2003
97. Ambrilia Biopharma, Inc. Pyrazolo[3,4- b]pyridin-2-yl-benzoic acid derivatives as HIB integrase inhibitors. WO2007000043; 2007
98. Wu JJ, Milot G, Dandache S, et al. Novel Small Inhibitors of HIV-1 Integrase. 16th International HIV Drug Resistance Workshop; 12 - 16 June 2007; Barbados
99. WU JJ, Milot G, Gouveia K, et al. Pyrazolopyridine Compounds as Novel HIV-1 Integrase Inhibitors. 47 th International Conference on Antimicrobial Agents and Chemotherapy, Sept 17-20 2007, Chicago, IL
100. Ambrilia Biopharma, Inc. HIV Integrase inhibitors from pyridoxine. WO2009146555; 2009
101. Avexa Ltd. Integrase Inhibitors 1. WO2007124544; 2007
102. Avexa Ltd. Integrase Inhibitors 2. WO2007124545; 2007
103. Avexa Ltd. Integrase Inhibitors 3. WO2007124546; 2007