Design and profiling of GS-9148, a novel nucleotide analog active against nucleoside-resistant variants of human immunodeficiency virus type 1, and its orally bioavailable phosphonoamidate prodrug, GS-9131

Antimicrobial Agents and Chemotherapy

Volumn 52, Issue 2, 2008, Pages 655-665

  Cihlar, Tomas ^a   Ray, Adrian S ^a   Boojamra, Constantine G ^a   Zhang, Lijun ^a   Hui, Hon ^a   Laflamme, Genevieve ^a   Vela, Jennifer E ^a   Grant, Deborah ^a   Chen, James ^a   Myrick, Florence ^b   White, Kirsten L ^a   Gao, Ying ^a   Lin, Kuei Ying ^a   Douglas, Janet L ^a   Parkin, Neil T ^c   Carey, Anne ^a   Pakdaman, Rowchanak ^a   Mackman, Richard L ^a  

^a GILEAD SCIENCES   (United States)

^b GILEAD SCIENCES INC   (United States)

^c MONOGRAM BIOSCIENCES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2',3' DIDEHYDRO 2',3' DIDEOXY 2' FLUORO 5' O PHOSPHONOMETHYLADENOSINE; [[[1 [(ETHOXYCARBONYL)ETHYL]AMINO]PHENOXYPHOSPHONYL]METHOXY] 2' FLUORO 1' FURANYLADENINE; ABACAVIR; DEOXYADENOSINE TRIPHOSPHATE; DIDANOSINE; DNA DIRECTED DNA POLYMERASE GAMMA; EFAVIRENZ; EMTRICITABINE; GS 9131; LOPINAVIR; LOPINAVIR PLUS RITONAVIR; PRODRUG; RIBAVIRIN; RNA DIRECTED DNA POLYMERASE; STAVUDINE; TENOFOVIR; UNCLASSIFIED DRUG; ZIDOVUDINE;

ANIMAL EXPERIMENT; ARTICLE; CELL TYPE; CONCENTRATION RESPONSE; CONTROLLED STUDY; CYTOTOXICITY; DOG; DRUG ACTIVITY; DRUG ANTAGONISM; DRUG BIOAVAILABILITY; DRUG DESIGN; DRUG HALF LIFE; DRUG POTENCY; DRUG POTENTIATION; DRUG STRUCTURE; ENZYME INHIBITION; GENE MUTATION; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS 1; IN VITRO STUDY; KIDNEY PROXIMAL TUBULE; MALE; MINIMUM INHIBITORY CONCENTRATION; MITOCHONDRIAL TOXICITY; NONHUMAN; PERIPHERAL BLOOD MONONUCLEAR CELL; PHOSPHORYLATION; PRIORITY JOURNAL; VIRUS INHIBITION; VIRUS ISOLATION; VIRUS RESISTANCE;

ADENINE; ANIMALS; ANTI-HIV AGENTS; CD4-POSITIVE T-LYMPHOCYTES; CELL LINE; DOGS; DRUG DESIGN; DRUG RESISTANCE, VIRAL; GUANOSINE; HIV-1; HUMANS; LEUKOCYTES, MONONUCLEAR; MACROPHAGES; MALE; MICROBIAL SENSITIVITY TESTS; PHOSPHONIC ACIDS; PRODRUGS; REVERSE TRANSCRIPTASE INHIBITORS;

EID: 38649089790     PISSN: 00664804     EISSN: None     Source Type: Journal    
DOI: 10.1128/AAC.01215-07     Document Type: Article

References (51)

1. Bethell, R. C., Y. S. Lie, and N. T. Parkin. 2005. In vitro activity of SPD754, a new deoxycytidine nucleoside reverse transcriptase inhibitor (NRTI), against 215 HIV-1 isolates resistant to other NRTIs. Antivir. Chem. Chemother. 16:295-302.
2. Birkus, G., M. J. Hitchcock, and T. Cihlar. 2002. Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob. Agents Chemother. 46:716-723.
3. Birkus, G., R. Wang, X. Liu, N. Kutty, H. MacArthur, T. Cihlar, C. Gibbs, S. Swaminathan, W. Lee, and M. McDermott. 2007. Cathepsin A is the major hydrolase catalyzing the intracellular hydrolysis of the antiretroviral nucleotide phosphonoamidate prodrugs GS-7340 and GS-9131. Antimicrob. Agents Chemother. 51:543-550.
4. Boojamra, C. G., R. L. Mackman, D. Y. Markevitch, V. Prasad, A. S. Ray, J. Douglas, D. Grant, C. U. Kim, and T. Cihlar. Bioorg. Med. Chem. Lett., in press.
5. Carr, A. 2003. Toxicity of antiretroviral therapy and implications for drug development. Nat. Rev. Drug Discov. 2:624-634.
6. Carr, A., J. Miller, M. Law, and D. A. Cooper. 2000. A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction associated with HIV nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy syndrome. AIDS 14:F25-F32.
7. Cherrington, J. M., S. J. W. Allen, N. Bischofberger, and M. S. Chen. 1995. Kinetic incorporation of the diphosphates of 9-(2-phosphonylmethoxyethyl) adenine and other anti-HIV active purine congeners with HIV reverse transcriptase and human DNA polymerases alpha, beta, and gamma. Antivir. Chem. Chemother. 6:217-221.
8. Cihlar, T., E. S. Ho, D. C. Lin, and A. S. Mulato. 2001. Human renal organic anion transporter 1 (hOAT1) and its role in the nephrotoxicity of antiviral nucleotide analogs. Nucleosides Nucleotides Nucleic Acids. 20:641-648.
9. Cihlar, T., A. Ray, C. Boojamra, L. Zhang, H. Hui, D. Grant, K. White, M. Desai, N. Parkin, and R. Mackman. 2006. GS9148: a novel nucleotide active against HIV-1 variants with drug resistance mutations in reverse transcriptase, abstr. 45. Abstr. 13th Conference on Retroviruses and Opportunistic Infections., Denver, CO.
10. De Clercq, E., and A. Holy. 2005. Acyclic nucleoside phosphonates: a key class of antiviral drugs. Nat. Rev. Drug Discov. 4:928-940.
11. Department of Health and Human Services. 10 October 2006, posting date. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. http://AIDSinfo.nih.gov.
12. Gallant, J. E., P. Z. Gerondelis, M. A. Wainberg, N. S. Shulman, R. H. Haubrich, M. St Clair, E. R. Lanier, N. S. Hellmann, and D. D. Richman. 2003. Nucleoside and nucleotide analogue reverse transcriptase inhibitors: a clinical review of antiretroviral resistance. Antivir. Ther. 8:489-506.
13. Geleziunas, R., K. Gallagher, H. Zhang, L. Bacheler, S. Garber, J. T. Wu, G. Shi, M. J. Otto, R. F. Schinazi, and S. Erickson-Viitanen. 2003. HIV-1 resistance profile of the novel nucleoside reverse transcriptase inhibitor beta-D-2′,3′-dideoxy-2′,3′-didehydro-5-fluorocytidine (Reverset). Antivir. Chem. Chemother. 14:49-59.
14. Geretti, A. M. 2007. Epidemiology of antiretroviral drug resistance in drugnaive persons. Curr. Opin. Infect. Dis. 20:22-32.
15. Graziewicz, M. A., M. J. Longley, R. J. Bienstock, M. Zeviani, and W. C. Copeland. 2004. Structure-function defects of human mitochondrial DNA polymerase in autosomal dominant progressive external ophthalmoplegia. Nat. Struct. Mol. Biol. 11:770-776.
16. Hawkins, T., W. Veikley, R. L. I. St. Claire, B. Guyer, N. Clark, and B. P. Kearney. 2005. Intracellular pharmacokinetics of tenofovir diphosphate, carbovir triphosphate, and lamivudine triphosphate in patients receiving triple-nucleoside regimens. J. Acquir. Immune Defic. Syndr. 39:406-411.
17. Holy, A. 2003. Phosphonomethoxyalkyl analogs of nucleotides. Curr. Pharm. Des. 9:2567-2592.
18. Huang, H., R. Chopra, G. L. Verdine, and S. C. Harrison. 1998. Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance. Science 282:1669-1675.
19. Kakuda, T. N. 2000. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochrondrial toxicity. Clin. Ther. 22:685-708.
20. Khandazhinskaya, A. L., E. A. Shirokova, Y. S. Skoblov, L. S. Victorova, L. Y. Goryunova, R. S. Beabealashvilli, T. R. Pronyaeva, N. V. Fedyuk, V. V. Zolin, A. G. Pokrovsky, and M. K. Kukhanova. 2002. Carbocyclic dinucleoside polyphosphonates: interaction with HIV reverse transcriptase and antiviral activity. J. Med. Chem. 45:1284-1291.
21. Kim, C., B. Luh, and J. C. Martin. 1991. Regiospecific and highly stereoselective electrophilic addition to furanoid glycals: synthesis of phosphonate nucleotide analogues with potent activity against HIV. J. Org. Chem. 56:2642-2647.
22. Kim, E. Y., L. Vrang, B. Oberg, and T. C. Merigan. 2001. Anti-HIV type 1 activity of 3′-fluoro-3′-deoxythymidine for several different multidrug-resistant mutants. AIDS Res. Hum. Retroviruses 17:401-407.
23. Kodama, E. I., S. Kohgo, K. Kitano, H. Machida, H. Gatanaga, S. Shigeta, M. Matsuoka, H. Ohrui, and H. Mitsuya. 2001. 4′-Ethynyl nucleoside analogs: potent inhibitors of multidrug-resistant human immunodeficiency virus variants in vitro. Antimicrob. Agents Chemother. 45:1539-1546.
24. Lacy, S. A., M. J. M. Hitchcock, W. A. Lee, P. Tellier, and K. C. Cundy. 1998. Effect of oral probenecid coadministration on the chronic toxicity and pharmacokinetics of intravenous cidofovir in cynomolgus monkeys. Toxicol. Sci. 4:97-106.
25. Lalezari, J. P., R. J. Stagg, B. D. Kuppermann, G. N. Holland, F. Kramer, D. V. Ives, M. Youle, M. R. Robinson, W. L. Drew, and H. S. Jaffe. 1997. Intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS. A randomized, controlled trial. Ann. Intern. Med. 126:257-263.
26. Lee, K., Y. Choi, G. Gumina, W. Zhou, R. F. Schinazi, and C. K. Cbu. 2002. Structure-activity relationships of 2′-fluoro-2′, 3′-unsaturated D-nucleosides as anti-HIV-1 agents. J. Med. Chem. 45:1313-1320.
27. Lee, W. A., G. X. He, E. Eisenberg, T. Cihlar, S. Swaminathan, A. Mulato, and K. C. Cundy. 2005. Selective intracellular activation of a novel prodrug of the human immunodeficiency virus reverse transcriptase inhibitor tenofovir leads to preferential distribution and accumulation in lymphatic tissue. Antimicrob. Agents Chemother. 49:1898-1906.
28. Longley, M. J., P. A. Ropp, S. E. Lim, and W. C. Copeland. 1998. Characterization of the native and recombinant catalytic subunit of human DNA polymerase gamma: identification of residues critical for exonuclease activity and dideoxynucleotide sensitivity. Biochemistry 37:10529-10539.
29. Mackman, R., C. Boojamra, J. Chen, J. Douglas, D. Grant, C. Kim, K. M. Lin, D., V. Prasad, A. Ray, and T. Cihlar. 2006. Discovery of GS-9148, a novel nucleotide HIV reverse transcriptase inhibitor. Antivir. Res. 70:A40.
30. Mackman, R. L., L. Zhang, V. Prasad, C. G. Boojamra, J. Douglas, D. Grant, H. Hui, C. U. Kim, G. Laflamme, J. Parrish, A. D. Stoycheva, S. Swaminathan, K. Wang, and T. Cihlar. 2007. Synthesis, anti-HIV activity, and resistance profile of thymidine phosphonomethoxy nucleosides and their bis-isopropyloxymethylcarbonyl (bisPOC) prodrugs. Bioorg. Med. Chem. 15:5519-5528.
31. Margot, N. A., and M. D. Miller. 2005. In vitro combination studies of tenofovir and other nucleoside analogues with ribavirin against HIV-1. Antivir. Ther. 10:343-348.
32. Moyle, G. 2000. Clinical manifestations and management of antiretroviral nucleoside analog-related mitochondrial toxicity. Clin. Ther. 22:911-936.
33. Nolan, D., and S. Mallal. 2004. Complications associated with NRTI therapy: update on clinical features and possible pathogenic mechanisms. Antivir. Ther. 9:849-863.
34. Ohrui, H., S. Kohgo, H. Hayakawa, E. Kodama, M. Matsuoka, T. Nakata, and H. Mitsuya. 2006. 2′-Deoxy-4′-C-ethynyl-2-fluoroadenosine: a nucleo-side reverse transcriptase inhibitor with highly potent activity against all HIV-1 strains, favorable toxic profiles and stability in plasma. Nucleic Acids Symp. Ser. 50:1-2.
35. Otto, M. J. 2004. New nucleoside reverse transcriptase inhibitors for the treatment of HIV infections. Curr. Opin. Pharmacol. 4:431-136.
36. Pillay, D., H. Green, R. Matthias, D. Dunn, A. Phillips, C. Sabin, and B. Evans. 2005. Estimating HIV-1 drug resistance in antiretroviral-treated individuals in the United Kingdom. J. Infect. Dis. 192:967-973.
37. Prichard, M. N., L. E. Prichard, W. A. Baguley, M. R. Nassiri, and C. Shipman, Jr. 1991. Three-dimensional analysis of the synergistic cytotoxicity of ganciclovir and zidovudine. Antimicrob. Agents Chemother. 35:1060-1065.
38. Prichard, M. N., and C. Shipman, Jr. 1990. A three-dimensional model to analyze drug-drug interactions. Antiviral Res. 14:181-205.
39. Ray, A. S., C. G. Boojamra, N. Parkin, K. L. White, G. R. Rhodes, R. Mackman, and T. Cihlar. 2006. Amidate prodrug of nucleotide analog GS-9148 has favorable in vitro activity against resistant HIV and in vivo pharmacokinetics. Global Antivir. J. 2(Suppl. 2):37.
40. Ray, A. S., J. E. Vela, C. G. Boojamra, L. Zhang, H. Hui, C. Callebaut, K. Stray, K.-Y. Lin, Y. Gao, R. L. Mackman, and T. Cihlar. 2008. Intracellular metabolism of the nucleotide prodrug GS-9131, a potent anti-human immunodeficiency virus agent. Antimicrob. Agents Chemother. 52:648-654.
41. Richman, D. D., S. C. Morton, T. Wrin, N. Hellmann, S. Berry, M. F. Shapiro, and S. A. Bozzette. 2004. The prevalence of antiretroviral drug resistance in the United States. AIDS 18:1393-1401.
42. Robbins, B., R. Srinivas, C. Kim, N. Bischofberger, and A. Fridland. 1998. Anti-human immunodeficiency virus activity and cellular metabolism of a potential prodrug of the acyclic nucleosides phosphate 9-R-(2-phosphonomethoxypropyl)adenine (PMPA), bis(isopropyloxymethylcarbonyl)PMPA. Antimicrob. Agents Chemother. 42:612-617.
43. Schinazi, R. F., J. Mellors, H. Bazmi, S. Diamond, S. Garber, K. Gallagher, R. Geleziunas, R. Klabe, M. Pierce, M. Rayner, J. T. Wu, H. Zhang, J. Hammond, L. Bacheler, D. J. Manien, M. J. Otto, L. Stuyver, G. Trainer, D. C. Liotta, and S. Erickson-Viitanen. 2002. DPC 817: a cytidine nucleoside analog with activity against zidovudine- and lamivudine-resistant viral variants. Antimicrob. Agents Chemother. 46:1394-1401.
44. Tamalet, C., J. Fantini, C. Tourres, and N. Yahi. 2003. Resistance of HIV-1 to multiple antiretroviral drugs in France: a 6-year survey (1997-2002) based on an analysis of over 7000 genotypes. AIDS 17:2383-2388.
45. Tsai, C. H., S. L. Doong, D. G. Johns, J. S. Driscoll, and Y. C. Cheng. 1994. Effect of anti-HIV 2′-beta-fluoro-2′,3′- dideoxynucleoside analogs on the cellular content of mitochondrial DNA and on lactate production. Biochem. Pharmacol. 48:1477-1481.
46. Vela, J. E., L. Y. Olson, A. Huang, A. Fridland, and A. S. Ray. 2007. Simultaneous quantitation of the nucleotide analog adefovir, its phosphorylated anabolites and 2′-deoxyadenosine triphosphate by ion-pairing LC/MS/MS. J. Chromatogr. B Anal. Technol Biomed. Life Sci. 848:335-343.
47. Wainberg, M. A., and D. Turner. 2004. Resistance issues with new nucleoside/nucleotide backbone options. J. Acquir. Immune Defic. Syndr. 37(Suppl. 1):S36-S43.
48. White, A. J. 2001. Mitochondrial toxicity and HIV therapy. Sex. Transm. Infect. 77:158-173.
49. White, K., J. Feng, A. Ray, G. Laflamme, F. Yu, M. Tsiang, R. Wang, M. McDermott, M. Miller, R. Mackman, and T. Cihlar. 2006. GS-9148 diphosphate, an active metabolite of a novel adenine nucleotide analogue, is an effective inhibitor of HIV-1 reverse transcriptase. Abstr. 46th Intersci. Conf. Antimicrob. Agents Chemother., abstr. H-251.
50. White, K. L., N. A. Margot, J. K. Ly, J. M. Chen, A. S. Ray, M. Pavelko, R. Wang, M. McDermott, S. Swaminathan, and M. D. Miller. 2005. A combination of decreased NRTI incorporation and decreased excision determines the resistance profile of HIV-1 K65R RT. AIDS 19:1751-1760.
51. Wu, T., M. Froeyen, V. Kempeneers, C. Pannecouque, J. Wang, R. Bussen, E. De Clercq, and P. Herdewijn. 2005. Deoxythreosyl phosphonate nucleosides as selective anti-HIV agents. J. Am. Chem. Soc. 127:5056-5065.