HIV Integrase Inhibitors: From Diketo Acids to Heterocyclic Templates: History of HIV Integrase Medicinal Chemistry at Merck West Point and Merck Rome (IRBM) Leading to Discovery of Raltegravir

HIV-1 Integrase: Mechanism and Inhibitor Design

Volumn , Issue , 2011, Pages 197-229

  Egbertson, Melissa S ^a   Anthony, Neville J ^a   Summa, Vincenzo ^b  

^a MERCK RESEARCH LABORATORIES   (United States)

^b Merck Research Laboratories   (Italy)

Author keywords

Heterocyclic rings; HIV integrase inhibitors; Polar heterocyclic substituents, 5 position

Indexed keywords

EID: 84886220106     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9781118015377.ch14     Document Type: Chapter

References (54)

1. Raltegravir. www.aidsinfo.nih.gov/DrugsNew/. 2007.
2. Pommier, Y.; Neamati, N. Inhibitors of human immunodeficiency virus integrase. Adv. Virus Res. 1999, 52, 427_458.
3. Hazuda, D. J.; Felock, P.; Witmer, M.; Wolfe, A.; Stillmock, K.; Grobler, J. A.; Espeseth, A.; Gabryelski, L.; Schleif, W.; Blau, C.; Miller, M. D. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 2000, 287, 646_650.
4. Hazuda, D. J.; Felock, P. J.; Hastings, J. C.; Pramanik, B.; Wolfe, A. L. Differential divalent cation requirements uncouple the assembly and catalytic reactions of human immunodeficiency virus type 1 integrase. J. Virol. 1997, 71, 7005_7011.
5. Ellison, V.; Brown, P. O. A stable complex between integrase and viral DNA ends mediates human immunodeficiency virus integration in vitro. Proc. Natl. Acad. Sci. USA 1994, 91, 7316_7320.
6. Parrill, A. L. HIV-1 integrase inhibition: Binding sites, structure activity relationships and future perspectives. Curr. Med. Chem. 2003, 10, 1811_1824.
7. Asante-Appiah, E.; Skalka, A. M. A metal-induced conformational change and activation of HIV-1 integrase. J. Biol. Chem. 1997, 272, 16196_16205.
8. Wolfe, A. L.; Felock, P. J.; Hastings, J. C.; Blau, C. U.; Hazuda, D. J. The role of manganese in promoting multimerization and assembly of human immunodeficiency virus type 1 integrase as a catalytically active complex on immobilized long terminal repeat substrates. J. Virol. 1996, 70, 1424_1432.
9. Hazuda, D. J.; Hastings, J. C.; Wolfe, A. L.; Emini, E. A. A novel assay for the DNA strand-transfer reaction of HIV-1 integrase. Nucleic Acids Res. 1994, 22, 1121_1122.
10. Vacca, J. P.; Dorsey, B. D.; Schleif, W. A.; Levin, R. B.; McDaniel, S. L.; Darke, P. L.; Zugay, J.; Quintero, J. C.; Blahy, O. M.; Roth, E.; Sardana, V. V.; Schlabach, A. J.; Graham, P. I.; Condra, J. H.; Gotlib, L.; Holloway, M. K.; Lin, J.; Chen, I. W.; Vastag, K.; Ostovic, D.; Anderson, P. S.; Emini, E. A.; Huff, J. R. L-735,524-An orally bioavailable human-immunodeficiency-virus type-1 protease inhibitor. Proc. Natl. Acad. Sci. 1994, 91, 4096_4100.
11. Selnick, H. G., Hazuda, D. J., Egbertson, M., Guare, J. P.,Wai, J. S., Young, S. D., Clark, D. L.; Medina, J. C. Preparation of nitrogen-containing 4-heteroaryl-2,4-dioxobutyric acids useful as HIV integrase inhibitors. Merck and Co., WO. 9962513 A1.
12. Hazuda, D. J.; Anthony, N. J.; Gomez, R. P.; Jolly, S. M.; Wai, J. S.; Zhuang, L.; Fisher, T. E.; Embrey, M.; Guare, J. P., Jr.; Egbertson, M. S.; Vacca, J. P.; Huff, J. R.; Felock, P. J.; Witmer, M. V.; Stillmock, K. A.; Danovich, R.; Grobler, J.; Miller, M. D.; Espeseth, A. S.; Jin, L.; Chen, I. W.; Lin, J. H.; Kassahun, K.; Ellis, J. D.;Wong, B. K.; Xu,W.; Pearson, P. G.; Schleif, W. A.; Cortese, R.; Emini, E.; Summa, V.; Holloway, M. K.; Young, S. D. A naphthyridine carboxamide provides evidence for discordant resistance between mechanistically identical inhibitors of HIV-1 integrase. Proc. Natl. Acad. Sci. USA 2004, 101, 11233_11238.
13. Wai, J. S.; Egbertson, M. S.; Payne, L. S.; Fisher, T. E.; Embrey, M. W.; Tran, L. O.; Melamed, J. Y.; Langford, H. M.; Guare, J. P., Jr.; Zhuang, L.; Grey, V. E.; Vacca, J. P.; Holloway, M. K.; Naylor-Olsen, A. M.; Hazuda, D. J.; Felock, P. J.; Wolfe, A. L.; Stillmock, K. A.; Schleif, W. A.; Gabryelski, L. J.; Young, S. D. 4-Aryl-2,4-dioxobutanoic acid inhibitors of HIV-1 integrase and viral replication in cells. J. Med. Chem. 2000, 43, 4923_4926.
14. Young, S. D., Wai, J. S., Embrey, M.; Fisher, T. E. Heterocyclyldioxobutanoates as HIV integrase inhibitors. Merck and Co., WO. 9962897 A1.
15. Trainor, G. L. The importance of plama protein binding in drug discovery. Expert Opin. Drug Discov. 2007, 2 (1), 51_64.
16. Young, S. D., Egbertson, M., Pearson, P. G., Wai, J. S., Fisher, T. E., Guare, J. P., Embrey, M. W., Tran, L. O., Zhuang, L., Vacca, J., Langford, H. M., Melamed, J., Clark, D. L., Medina, J. C.; Jaen, J. Preparation of aromatic and heteroaromatic 4-aryl-2,4-dioxobutyric acid derivatives useful as HIV integrase inhibitors. Merck and Co., WO. 9962520 A1.
17. Espeseth, A. S.; Felock, P.;Wolfe, A.;Witmer, M.; Grobler, J.; Anthony, N.; Egbertson, M.; Melamed, J. Y.; Young, S.; Hamill, T.; Cole, J. L.; Hazuda, D. J. 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_11249.
18. Grobler, J. A.; Stillmock, K.; Hu, B.; Witmer, M.; Felock, P.; Espeseth, A. S.; Wolfe, A.; Egbertson, M.; Bourgeois, M.; Melamed, J.; Wai, J. S.; Young, S.; Vacca, J.; Hazuda, D. J. Diketo acid inhibitor mechanism and HIV-1 integrase: Implications for metal binding in the active site of phosphotransferase enzymes. Proc. Natl. Acad. Sci. USA 2002, 99, 6661_6666.
19. Payne, L. S., Tran, L. O., Zhuang, L., Young, S. D., Egbertson, M., Wai, J. S., Embrey, M. W., Fisher, T. E., Guare, J. P., Langford, H. M., Melamed, J.; Clark, D. L. Preparation of 1,3-diaryl-1,3-propanediones as HIV integrase inhibitors. Merck & Co. and Tularik, Inc., WO. 2001000578 A1.
20. Fujishita, T.; Yoshinaga, T.; Sato, A. Preparation of aromatic heterocycle compounds having HIV integrase inhibiting activities. Shionogi and Co., Japan. WO. 2000039086 A1.
21. Uenaka, M.; Kawata, K.; Nagai, M.; Endoh, T. Novel processes for the preparation of substituted propenone derivatives. Shionogi & Co., Japan. WO. 2000075122.
22. Goldgur, Y.; Craigie, R.; Cohen, G. H.; Fujiwara, T.; Yoshinaga, T.; Fujishita, T.; Sugimoto, H.; Endo, T.; Murai, H.; Davies, D. R. Structure of the HIV-1 integrase catalytic domain complexed with an inhibitor: A platform for antiviral drug design. Proc. Natl. Acad. Sci. 1999, 96 (23), 13040_13043.
23. Yoshinaga, T.; Fujishita, T.; Fujiwara, T. S-1360: In vitro activity of a new HIV-1 integrase inhibitor in clinical development. Paper presented at the 9th Conference on Retroviruses and Opportunistic Infections, Seattle, 2002.
24. Leese, P.; Lippert, C.; Russell, T.; Fujiwara, T. S-1360: A new HIV integrase inhibitor. repeat dose pharmacokinetics and safety in healthy volunteers following oral administration. Paper presented at the XIV international AIDS Conference, Barcelona, Spain, 2002.
25. Anthony, N. J. HIV-1 integrase: A target for new AIDS chemotherapeutics. Curr. Top. Med. Chem. 2004, 4, 979_990.
26. Goldgur, Y.; Dyda, F.; Hickman, A. B.; Jenkins, T. M.; Craigie, R.; Davies, D. R. Three new structures of the core domain of HIV-1 integrase: An active site that binds magnesium. Proc. Natl. Acad. Sci. USA 1998, 95 (16), 9150_9154.
27. Albert, A.; Hampton, A. Analogues of 8-hydroxyquinoline having additional cyclic nitrogen atoms. Part II. Further preparations, and some physico-chemical properties. J. Chem. Soc. 1954, 505_513.
28. Zhuang, L.; Wai, J. S.; Embrey, M. W.; Fisher, T. E.; Egbertson, M. S.; Payne, L. S.; Guare, J. P., Jr.; Vacca, J. P.; Hazuda, D. J.; Felock, P. J.; Wolfe, A. L.; Stillmock, K. A.; Witmer, M. V.; Moyer, G.; Schleif, W. A.; Gabryelski, L. J.; Leonard, Y. M.; Lynch, J. J., Jr.; Michelson, S. R.; Young, S. D. Design and synthesis of 8-hydroxy-[1,6]naphthyridines as novel inhibitors of HIV-1 integrase in vitro and in infected cells. J. Med. Chem. 2003, 46, 453_456.
29. Zhuang, L.; Wai, J. S., Payne, L. S., Young, S. D., Fisher, T. E., Embrey, M.; Guare, J. P. Preparation of aza- and polyazanaphthalenyl ketones useful as HIV integrase inhibitors. Merck & Co., WO. 2002036734 A1.
30. Pace, P.; Nizi, E.; Pacini, B.; Pesci, S.; Matassa, V.; De Francesco, R.; Altamura, S.; Summa, V. The monoethyl ester of meconic acid is an active site inhibitor of HCV NS5B RNA-dependent RNA polymerase. Bioorg. Med. Chem. Lett. 2004, 14 (12), 3257_3261.
31. Summa, V.; Petrocchi, A.; Pace, P.; Matassa, V. G.; De Francesco, R.; Altamura, S.; Tomei, L.; Koch, U.; Neuner, P. Discovery of a,g-diketo acids as potent selective and reversible inhibitors of hepatitis C virus NS5b RNA-dependent RNA polymerase. J. Med. Chem. 2004, 47 (1), 14_17.
32. Petrocchi, A.; Koch, U.; Matassa, V. G.; Pacini, B.; Stillmock, K. A.; Summa, V. From dihydroxypyrimidine carboxylic acids to carboxamide HIV-1 integrase inhibitors: SAR around the amide moiety. Bioorg. Med. Chem. Lett. 2007, 17, 350_353.
33. Summa, V.; Petrocchi, A.; Matassa, V. G.; Taliani, M.; Laufer, R.; De Francesco, R.; Altamura, S.; Pace, P. HCV NS5b RNA-dependent RNA polymerase inhibitors: From a,g-diketoacids to 4,5-dihydroxypyrimidine- or 3-methyl-5-hydroxypyrimidinonecarboxylic acids. Design and synthesis. J. Med. Chem. 2004, 47 (22), 5336_5339.
34. Petrocchi, A.; Pace, P.; Hazuda, D.; Schleif, W. A.; Stillmock, K. A.; Witmer, M. V.; Matassa, V. G.; Summa, V. From dihydroxypyrimidine carboxylic acids to carboxamide HIV integrase inhibitors. Abstracts of Papers. Presented at the 230th ACS National Meeting, Washington, DC, August 28_September 1, 2005. MEDI-185, 2005.
35. Summa, V.; Petrocchi, A.; Matassa, V. G.; Gardelli, C.; Muraglia, E.; Rowley, M.; Paz, O. G.; Laufer, R.; Monteagudo, E.; Pace, P. 4,5-Dihydroxypyrimidine carboxamides and N-alkyl-5-hydroxypyrimidinone carboxamides are potent, selective HIV integrase inhibitors with good pharmacokinetic profiles in preclinical species. J. Med. Chem. 2006, 49, 6646_6649.
36. Anthony, N. J.; Gomez, R. P.; Young, S. D.; Egbertson, M.; Wai, J. S.; Zhuang, L.; Embrey; M., Tran, L. O.; Melamed, J.; Langford, H. M.; Guare, J. P.; Fisher, T. E.; Jolly, S. M.; Kuo, M. S.; Perlow, D. S.; Bennett, J. J.; Funk, T. W. Preparation of (poly)azanaphthalenyl carboxamides as HIV integrase inhibitors. Merck & Co., WO. 2002030930 A1.
37. Guare, J. P.; Wai, J. S.; Gomez, R. P.; Anthony, N. J.; Jolly, S. M.; Cortes, A. R.; Vacca, J. P.; Felock, P. J.; Stillmock, K. A.; Schleif, W. A.; Moyer, G.; Gabryelski, L. J.; Jin, L.; Chen, I. W.; Hazuda, D. J.; Young, S. D. A series of 5-aminosubstituted 4-fluorobenzyl-8-hydroxy-[1,6]naphthyridine-7-carboxamide HIV-1 integrase inhibitors. Bioorg. Med. Chem. Lett. 2006, 16, 2900_2904.
38. Chapman, R. G.; Ostuni, E.; Takayama, S.; Holmlin, R. E.; Yan, L.; Whitesides, G. M. Surveying for surfaces that resist the adsorption of proteins. J. Am. Chem. Soc. 2000, 122 (34), 8303_8304.
39. Mulder, G. J.; Van Doorn, A. B. D. Rapid NAD-linked assay for microsomal uridine diphosphate glucuronyltransferase of rat liver and observations on substrate specificity of the enzyme. Biochem. J. 1975, 151 (1), 131_140.
40. Hazuda, D. J.; Young, S. D.; Guare, J. P.; Anthony, N. J.; Gomez, R. P.; Wai, J. S.; Vacca, J. P.; Handt, L.; Motzel, S. L.; Klein, H. J.; Dornadula, G.; Danovich, R. M.; Witmer, M. V.; Wilson, K. A.; Tussey, L.; Schleif, W. A.; Gabryelski, L. S.; Jin, L.; Miller, M. D.; Casimiro, D. R.; Emini, E. A.; Shiver, J. W. Integrase inhibitors and cellular immunity suppress retroviral replication in rhesus macaques. Science 2004, 305, 528_532.
41. Egbertson, M., Melamed, J.; Young, S. Hydroxynaphthyridinone carboxamides useful as HIV integrase inhibitors. WO 2003062204[US 20050119482 A1].
42. Itai, A.; Toriumi, Y.; Saito, S.; Kagechika, H.; Shudo, K. Preference of cis-amide structure in N-acyl-N-methylanilines. J. Am. Chem. Soc. 1992, 114, 10649_10650.
43. Little, S. J.; Drusano, G.; Schooly, R.; Haas, D. W.; Kumar, P.; Hammer, S.; McMahon, D.; Squires, K.; Asfour, R.; Richman, D.; Chen, J.; Saah, A.; Leavitt, R.; Hazuda, D. J.; Nguyen, B.-Y. Protocol 004. Paper presented at the 12th Conference on Retroviruses and Opportunistic Infections, February 22, 2005. Boston, Mass. USA
44. Embrey, M. W.; Wai, J. S.; Funk, T. W.; Homnick, C. F.; Perlow, D. S.; Young, S. D.; Vacca, J. P.; Hazuda, D. J.; Felock, P. J.; Stillmock, K. A.; Witmer, M. V.; Moyer, G.; Schleif, W. A.; Gabryelski, L. J.; Jin, L.; Chen, I.W.; Ellis, J. D.;Wong, B. K.; Lin, J. H.; Leonard, Y. M.; Tsou, N. N.; Zhuang, L. A series of 5-(5,6)-dihydrouracil substituted 8-hydroxy-[1,6] naphthyridine-7-carboxylic acid 4-fluorobenzylamide inhibitors of HIV-1 integrase and viral replication in cells. Bioorg. Med. Chem. Lett. 2005, 15, 4550_4554.
45. Horn, T. HIV drug resistance and drug-resistance testing: Just the FAQs. The body: The complete HIV/AIDS resource. 2001. www.thebody.com
46. Egbertson, M.; Langford, H. M.; Melamed, J.; Wai, J. S.; Han, W.; Perlow, D. S.; Zhuang, L.; Embrey, M.; Young, S. D. Preparation of N-(substituted benzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamides useful as HIV integrase inhibitors for treatment of HIV infection/AIDS. Merck & Co., WO. 2003077857.
47. Egbertson, M. S.; Moritz, H. M.; Melamed, J. Y.; Han, W.; Perlow, D. S.; Kuo, M. S.; Embrey, M.; Vacca, J. P.; Zrada, M. M.; Cortes, A. R.; Wallace, A.; Leonard, Y.; Hazuda, D. J.; Miller, M. D.; Felock, P. J.; Stillmock, K. A.; Witmer, M. V.; Schleif, W.; Gabryelski, L. J.; Moyer, G.; Ellis, J. D.; Jin, L. X.; Xu, W.; Braun, M. P.; Kassahun, K.; Tsou, N. N.; Young, S. D. A potent and orally active HIV-1 integrase inhibitor. Bioorg. Med. Chem. Lett. 2007, 17, 1392_1398.
48. Pace, P.; Di Francesco, M. E.; Gardelli, C.; Harper, S.; Muraglia, E.; Nizi, E.; Orvieto, F.; Petrocchi, A.; Poma, M.; Rowley, M.; Scarpelli, R.; Laufer, R.; Paz, O. G.; Monteagudo, E.; Bonelli, F.; Hazuda, D.; Stillmock, K. A.; Summa, V. Dihydroxypyrimidine-4-carboxamides as novel potent and selective HIV integrase inhibitors. J. Med. Chem. 2007, 50, 2225_2239.
49. Gardelli, C.; Nizi, E.; Muraglia, E.; Crescenzi, B.; Ferrara, M.; Orvieto, F.; Pace, P.; Pescatore, G.; Poma, M.; Ferreira, M. D. R. R.; Scarpelli, R.; Homnick, C. F.; Ikemoto, N.; Alfieri, A.; Verdirame, M.; Bonelli, F.; Paz, O. G.; Taliani, M.; Monteagudo, E.; Pesci, S.; Laufer, R.; Felock, P.; Stillmock, K. A.; Hazuda, D.; Rowley, M.; Summa, V. Discovery and synthesis of HIV integrase inhibitors: Development of potent and orally bioavailable N-methyl pyrimidones. J. Med. Chem. 2007, 50, 4953_4975.
50. Summa, V. Discovery, synthesis and optimization of a new series of selective HIV integrase inhibitors leading to MK-0518 currently in Phase III clinical trial for treatment of HIV/AIDS. Abstract of Papers. Presented at the 232nd ACS National Meeting, San Francisco, CA. MEDI-298 September 10, 2006.
51. Crescenzi, B.; Gardelli, C.; Mruaglia, E.; Nizi, E.; Orvieto, F.; Pace, P.; Pescatore, G.; Petrocchi, A.; Poma, M.; Rowley, M.; Sarpelli, R.; Summa, V. Preparation of N-substituted hydroxypyrimidinone carboxamide inhibitors of HIV integrase. WO 2003035077 A1.
52. Summa, V.; Petrocchi, A.; Scarpelli, R.; Gardelli, C.; Muraglia, E.; Nizi, E.; Laufer, R.; Gonzalez Paz, O.; Fiore, F.; Jones, P.; Monteagudo, E.; Hazuda, D.; Witmer, M.; Rowley, M. Discovery of ISENTRESSTM a potent, selctive orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection. J. Med. Chem. 2008, 51 (18), 5843-5855.
53. Monteagudo, E.; Pesci, S.; Taliani, M.; Fiore, F.; Petrocchi, A.; Nizi, E.; Rowley, M.; Laufer, R.; Summa, V. Studies of metabolism and disposition of potent human immunodeficiency virus (HIV) integrase inhibitors using F-19-NMR spectroscopy. Xenobiotica 2007, 37, 1000_1012.
54. Markowitz, M.; Morales-Ramirez, J. O.; Nguyen, B. Y.; Kovacs, C. M.; Steigbigel, R. T.; Cooper, D. A.; Liporace, R.; Schwartz, R.; Isaacs, R.; Gilde, L. R.; Penning, L.; Zhao, J.; Teppler, H. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. J. AIDS 2006, 43, 509_515