Dihydroxy-pyrimidine and N-methylpyrimidone HIV-integrase inhibitors: Improving cell based activity by the quaternarization of a chiral center

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 16, 2009, Pages 4617-4621

  Nizi, Emanuela ^a   Orsale, Maria Vittoria ^a   Crescenzi, Benedetta ^a   Pescatore, Giovanna ^a   Muraglia, Ester ^a   Alfieri, Anna ^a   Gardelli, Cristina ^a   Spieser, Stéphane A H ^a   Summa, Vincenzo ^a  

^a IRBM   (Italy)

Author keywords

HIV 1 integrase; N Methylpyrimidones; PAMPA; Pyrimidines

Indexed keywords

INTEGRASE INHIBITOR; PYRIMIDINE DERIVATIVE; PYRIMIDINONE DERIVATIVE;

ANIMAL EXPERIMENT; ARTICLE; CHEMICAL MODIFICATION; CHIRALITY; CONTROLLED STUDY; DRUG ACTIVITY; DRUG STRUCTURE; HUMAN IMMUNODEFICIENCY VIRUS; MEMBRANE PERMEABILITY; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION;

ANIMALS; CELL MEMBRANE PERMEABILITY; HIV INTEGRASE; HIV INTEGRASE INHIBITORS; HUMANS; PROTEIN BINDING; PYRIMIDINES; PYRIMIDINONES; RATS;

HUMAN IMMUNODEFICIENCY VIRUS 1; RATTUS;

EID: 67749116233     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.06.091     Document Type: Article

References (27)

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., and Delaporte E.J. Acq. Imm. Defic. Syndr. 38 (2005) 14
3. Esposito D., and Craige R. Adv. Virus Res. 52 (1999) 351
4. Hazuda D.J., Felock P.J., Witmer M., Wolfe A., Stillmock K., Grobler J.A., Espeseth A., Gabryelski L., Schleif W., Blau C., and Miller M.D. Science 287 (2000) 646
5. Gordon C.P., Griffith R., and Keller P.A. Med. Chem. 3 (2007) 199
6. Pommier Y., Johnson A.A., and Marchand C. Nat. Rev. Drug Disc. 4 (2005) 236
7. Summa V., Petrocchi A., Matassa V.G., Gardelli C., Muraglia E., Rowley M., Gonzalez Paz O., Laufer R., Monteagudo E., and Pace P. J. Med. Chem. 49 (2006) 6646
8. 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., and Rowley M. J. Med. Chem. 50 (2007) 4953
9. 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., and Summa V. J. Med. Chem. 50 (2007) 2225
10. 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., and Rowley M. J. Med. Chem. 51 (2008) 5843
11. Pye P.J., Zhong Y.-L., Jones G.O., Reamer R.A., Houk K.N., and Askin D. Angew. Chem., Int. Ed. 47 (2008) 4134
12. Synthesis of the nitrile 4a:. Beck A.K., Blank S., Job K., Seebach D.E., and Sommerfeld T. Org. Synth. 72 (1995) 62
13. Synthesis of the nitrile 5a:. Wolckenhauer S.A., and Rychnovsky S.D. Org. Lett. 6 (2004) 2745
14. For the synthesis of the nitrile 8a: see Ref. 8 (Supporting Information).
15. P-value <0.05 is considered as statistically significant.
16. Hazuda D.J., Felock P.J., Hastings J.C., Pramanik B., and Wolfe A.L. J. Virol. 71 (1997) 7005
17. Zhuang L., Wai J.S., Embrey M.W., Fisher T.S., Egbertson M.S., Payne L.P., 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
18. 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., and Roth E. Proc. Natl. Acad. Sci. U.S.A. 91 (1994) 4096
19. 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)* standard concentration.
20. Pan L., Ho Q., Tsutsui K., and Takahashi L. J. Pharm. Sci. 90 (2001) 521
21. Kansy M., Senner F., and Gubernator K. J. Med. Chem. 41 (1998) 1007
22. 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., and Cheng K.-C. Biochem. Pharmacol. 75 (2008) 1186
23. Avdeef A. Absorption and drug development (2003), Wiley-Interscience pp 42-66
24. Henchoz Y., Guillarme D., Rudaz S., Veuthey J.-L., and Carrupt P.-A. J. Med. Chem. 51 (2008) 396
25. 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.
26. Chen X., Murawski K.P., Crespi C.L., and Balimane P.V. Pharm. Res. 25 (2008) 1511
27. Faller B. Curr. Drug Metab. 9 (2008) 886