E. Nizi et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4617–4621
12. P-value <0.05 is considered as statistically significant.
4621
References and notes
13. (a) Hazuda, D. J.; Felock, P. J.; Hastings, J. C.; Pramanik, B.; Wolfe, A. L. J. Virol.
1997, 71, 7005; (b) Zhuang, L.; Wai, J. S.; Embrey, M. W.; Fisher, T. S.; Egbertson,
M. S.; Payne, L. P.; 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. J. Med. Chem. 2003,
46, 453.
14. 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. Proc. Natl. Acad. Sci. U.S.A. 1994,
91, 4096.
15. (a) The method is based on HPLC UV–vis protocol where injections of both a
standard solution (DMSO and organic co-solvents) and the sample (stock
DMSO solution diluted with PBS) are performed after centrifugation and
filtration. After a 1.5 min fast method gradient run (ACN vs PBS) of both
standard and sample the integration of the peak area of each injections
afforded the solubility value. Solubility = (peak area of sample/peak area of
standard)ꢃ standard concentration.; (b) Pan, L.; Ho, Q.; Tsutsui, K.; Takahashi, L.
J. Pharm. Sci. 2001, 90, 521.
16. Kansy, M.; Senner, F.; Gubernator, K. J. Med. Chem. 1998, 41, 1007.
17. Li, C.; Naira, L.; Liua, T.; Lia, F.; Pichardoa, J.; Agrawala, S.; Chasea, R.; Tonga, X.
S.; Ussa, A.; Bogena, S.; Njorogea, G.; Morrisona, R.; Cheng, K.-C. Biochem.
Pharmacol. 2008, 75, 1186.
18. Avdeef, A. Absorption and drug development; Wiley-Interscience, 2003. pp 42–
66.
19. Henchoz, Y.; Guillarme, D.; Rudaz, S.; Veuthey, J.-L.; Carrupt, P.-A. J. Med. Chem.
2008, 51, 396.
20. The test compound is dissolved in a pH 7.4 buffer and incubated with human
plasma at 37 °C for 1 h. The mixture is then spun in an ultrafiltration device
and the filtrate is assayed for free drug by analytical HPLC–UV detection.
21. Chen, X.; Murawski, K. P.; Crespi, C. L.; Balimane, P. V. Pharm. Res. 2008, 25,
1511.
1. UNAIDS 2008 Report on the Global AIDS Epidemic.
2. Laurent, C.; Gueye, N. F. N.; Ndour, C. T.; Gueye, P. M.; Diouf, M.; Diakhatè, N.;
Kane, N. C. T.; Lanièce, I.; Ndir, A.; Vergne, L.; Ndoye, I.; Mboup, S.; Sow, P. S.;
Delaporte, E. J. Acq. Imm. Defic. Syndr. 2005, 38, 14.
3. Esposito, D.; Craige, R. Adv. Virus Res. 1999, 52, 351.
4. (a) Hazuda, D. J.; Felock, P. J.; Witmer, M.; Wolfe, A.; Stillmock, K.; Grobler, J. A.;
Espeseth, A.; Gabryelski, L.; Schleif, W.; Blau, C.; Miller, M. D. Science 2000, 287,
646; (b) Gordon, C. P.; Griffith, R.; Keller, P. A. Med. Chem. 2007, 3, 199.
5. Pommier, Y.; Johnson, A. A.; Marchand, C. Nat. Rev. Drug Disc. 2005, 4, 236.
6. Summa, V.; Petrocchi, A.; Matassa, V. G.; Gardelli, C.; Muraglia, E.; Rowley, M.;
Gonzalez Paz, O.; Laufer, R.; Monteagudo, E.; Pace, P. J. Med. Chem. 2006, 49,
6646.
7. Gardelli, C.; Nizi, E.; Muraglia, E.; Crescenzi, B.; Ferrara, M.; Orvieto, F.; Pace, P.;
Pescatore, G.; Poma, M.; Rico Ferreira, M.; Scarpelli, R.; Homnick, C. F.; Alfieri,
A.; Bonelli, F.; Gonzalez Paz, O.; Monteagudo, E.; Pesci, S.; Laufer, R.; Stillmock,
K. A.; Hazuda, D.; Summa, V.; Rowley, M. J. Med. Chem. 2007, 50, 4953.
8. 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.;
Gonzalez, P. O.; Monteagudo, E.; Bonelli, F.; Hazuda, D.; Stillmock, K. A.;
Summa, V. J. Med. Chem. 2007, 50, 2225.
9. Summa, V.; Petrocchi, A.; Bonelli, F.; Crescenzi, B.; Donghi, M.; Ferrara, M.; Fiore,
F.; Gardelli, C.; Gonzalez Paz, O.; Hazuda, D. J.; Jones, P.; Kinzel, O.; Laufer, R.;
Monteagudo, E.; Muraglia, E.; Nizi, E.; Orvieto, F.; Pace, P.; Pescatore, G.; Scarpelli,
R.; Stillmock, K. A.; Witmer, M. V.; Rowley, M. J. Med. Chem. 2008, 51, 5843.
10. Pye, P. J.; Zhong, Y.-L.; Jones, G. O.; Reamer, R. A.; Houk, K. N.; Askin, D. Angew.
Chem., Int. Ed. 2008, 47, 4134.
11. Synthesis of the nitrile 4a: (a) Beck, A. K.; Blank, S.; Job, K.; Seebach, D. E.;
Sommerfeld, T. Org. Synth. 1995, 72, 62; Synthesis of the nitrile 5a: (b)
Wolckenhauer, S. A.; Rychnovsky, S. D. Org. Lett. 2004, 6, 2745; (c) For the
synthesis of the nitrile 8a: see Ref. 8 (Supporting Information).
22. Faller, B. Curr. Drug Metab. 2008, 9, 886.