A potent and orally active HIV-1 integrase inhibitor

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 5, 2007, Pages 1392-1398

  Egbertson, Melissa S ^a   Moritz, H Marie ^a   Melamed, Jeffrey Y ^a   Han, Wei ^a   Perlow, Debra S ^a   Kuo, Michelle S ^a   Embrey, Mark ^a   Vacca, Joseph P ^a   Zrada, Matthew M ^a   Cortes, Amanda R ^a   Wallace, Audrey ^a   Leonard, Yvonne ^a   Hazuda, Daria J ^a   Miller, Michael D ^a   Felock, Peter J ^a   Stillmock, Kara A ^a   Witmer, Marc V ^a   Schleif, William ^a   Gabryelski, Lori J ^a   Moyer, Gregory ^a   Ellis, Joan D ^a   Jin, Lixia ^a   Xu, Wei ^a   Braun, Matthew P ^a   Kassahun, Kellem ^a   Tsou, Nancy N ^b   Young, Steven D ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

^b Department of Medicinal Chemistry ^*  (United States)

Author keywords

1,6 Naphthyridine; AIDS; HIV; Integrase; Strand transfer

Indexed keywords

INTEGRASE INHIBITOR; L 900564; N (4 FLUOROBENZYL) 8 HYDROXY 5 (TETRAHYDRO 2H 1,2 THIAZIN 2 YL) 1,6 NAPHTHYRIDINE 7 CARBOXAMIDE S,S DIOXIDE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANTIVIRAL ACTIVITY; ARTICLE; CONTROLLED STUDY; DRUG DESIGN; DRUG INHIBITION; DRUG POTENCY; DRUG STRUCTURE; IC 50; NONHUMAN; RAT; STRUCTURE ANALYSIS; VIRUS INHIBITION;

ADMINISTRATION, ORAL; ANIMALS; CELLS, CULTURED; HIV INTEGRASE; HIV INTEGRASE INHIBITORS; HUMANS; INHIBITORY CONCENTRATION 50; MUTATION; NAPHTHYRIDINES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP;

HUMAN IMMUNODEFICIENCY VIRUS 1;

EID: 33846916481     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.11.080     Document Type: Article

References (21)

1. For a recent review on the structure and function of HIV-1 IN, see: (a). Chiu T.K., and Davies D.R. Curr. Top. Med. Chem. 4 (2004) 965
2. Pommier Y., Johnson A.A., and Marchand C. Nat. Rev. Drug Disc. 4 (2005) 236
3. For a recent review on HIV-1 IN inhibitors, see:. Anthony N.J. Curr. Top. Med. Chem. 4 (2004) 979
4. Zhuang L., Wai J.S., Embrey M.W., Fisher T.E., Egbertson M.S., Payne L.S., Guare Jr. J.P., 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 Jr. J.J., Michelson S.R., and Young S.D. J. Med. Chem. 46 (2003) 453
5. Hazuda D.J., Anthony N.J., Gomez R.P., Jolly S.M., Wai J.S., Zhuang L., Fisher T.E., Embrey M.W., Guare Jr. J.P., 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., 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., and Young S.D. Proc. Natl. Acad. Sci. U.S.A. 101 (2004) 11233
6. Little, S.J.; Drusano, G.; Schooley, R.; Haas, D.W.; Kumar, P.; Hammer, S.; McMahon, D.; Squires, K.; Asfour, R.; Richman, D.; Chen, J.; Saah, A.; Leavitt, R.; Hazuda, D.; Nguyen, B.-Y. for Protocol 004 Study Team, 12th Conference on Retroviruses and Opportunistic Infections, Feb. 22-25, 2005, Boston, MA, Abstract 161.
7. D, dissociation constant.
8. 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., Schlabac 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.E., and Huff J.R. Proc. Natl. Acad. Sci. U.S.A. 91 (1994) 4096
9. 4/NaOH) water layer. HPLC methods are based on the maximum absorbance of each compound. Log P = log (Octanol HPLC area)(Octanol dilution)/(Buffer HPLC area)(buffer dilution).
10. Solubility determination protocol. A suspension of crystalline drug in 10 mM, pH 7.4, sodium phosphate buffer was allowed to equilibrate at room temperature for 5 days. Aliquots of the suspension were centrifuged at 15,000 rpm for 15 min. The solution drug concentration determined by HPCL at day 2 and 5 is taken as the solubility value.
11. Chapman R.G., Ostuni E., Takayama S., Holmlin R.E., Yan L., and Whitesides G.M. J. Am. Chem. Soc. 122 (2000) 8303
12. Anthony, N. J.; Gomez, R. P.; Young, S. D.; Egbertson, M.; Wai, J. S.; Zhuang, L.; Embrey, M.; Tran, L.; Melamed, J. Y.; 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 IN inhibitors. PCT Int. Appl. (2002), 434 pp. WO 0230930 A2 20020418.
13. Egbertson, M.; Langford, H. M.; Melamed, J. Y.; Wai, J. S.; Han, W.; Perlow, D. S.; Zhuang, L.; Embrey, M.; Young, S. D. N-(substituted benzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamides useful as HIV IN inhibitors US20050176955 A1.
14. 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 Jr. J.P., 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., and Young S.D. J. Med. Chem. 43 (2000) 4923
15. Perlow, D. S.; Kuo, M. S.; Moritz, H. M.; Wai, J. S.; Egbertson, M. S. Syn. Comm. 2007, 37, in press.
16. Maybridge Chemicals.
17. Protein binding determination with radiolabeled material. An ultracentrifugation method was used to determine the unbound fraction of radiolabeled compound in human plasma. Plasma (pH adjusted to 7.4) was treated with compound to yield final concentrations of 1, 5, and 20 μM. Following incubation at 37 °C for 30 min, aliquots of plasma were transferred immediately to 1.5 mL polyallomer centrifuge tubes. The tubes were centrifuged at 37 °C and 180,000g overnight (∼18 h) using a high-speed centrifuge (Beckman Optima™, Model TLX). A six- or eight-place, fixed-angle rotor (TLA-100.3 or TLA-100.4) was used. Aliquots (0.2 mL each) of the supernatant were removed sequentially. Radioactivity in supernatants and original plasma samples was determined by liquid scintillation spectrometry with quench correction by external standardization. The percent unbound fraction (fu) was calculated as follows: fu (%) = dpm in protein-free section/dpm in original plasma × 100%.
18. Compounds 22 and 23 were prepared in a manner similar to that described for 21b. See Ref. 9 for experimental details.
19. 14C labeled 3, which was coupled as described above to give the final compounds.
20. The sodium salts were ground in a mortar and pestle, and dosed orally as an aqueous solution/suspension in 1% aq methylcellulose in rats (10 mg/kg). In dogs and rhesus monkeys 0.5% aq methylcellulose suspensions were dosed at 1 mg/kg. Compound was dosed intravenously dissolved in dimethylsulfoxide (DMSO) at concentrations of 2 mg/kg in rats and 1 mg/kg in dogs and rhesus.
21. Crystallographic data (excluding structure factors) for 21b have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number 619397. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB@ 1EZ, UK [Fax: +44 1223 336033 or email: depost@ccdc.cam.ac.uk].