A. Gagnon et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4437–4441
4441
A.; Carpenter, C. C. J.; Fischl, M. A.; Gazzard, B. G.;
Gatell, J. M.; Hirsch, M. S.; Katzenstein, D. A.; Richman,
D. D.; Vella, S.; Yeni, P. G.; Volberding, P. A. J. Am.
Med. Assoc. (JAMA) 2006, 296, 827.
12. O’Meara, J. A.; Jakalian, A.; LaPlante, S.; Bonneau, P.
R.; Coulombe, R.; Faucher, A.-M.; Guse, I.; Landry, S.;
Racine, J.; Simoneau, B.; Thavonekham, B.; Yoakim, C.
Bioorg. Med. Chem. Lett. 2007, 17, 3362.
´
3. Johnson, V. A.; Brun-Vezinet, F.; Clotet, B.; Conway, B.;
13. Simoneau, B.; Thavonekham, B.; Landry, S.; O’Meara,
J.; Yoakim, C.; Faucher, A.-M. 2004 WO 2004/
050643.
D’Aquila, R. T.; Demeter, L. M.; Kuritzkes, D. R.; Pillay,
D.; Schapiro, J. M.; Telenti, A.; Richman, D. D. Top. HIV
Med. 2003, 11, 215.
14. (a) Girardet, J. L.; Zhang, Z.; Hamatake, R.; Hernandez,
M. A. De la Rosa; Gunic, E.; Hong, Z.; Kim, H; Koh, Y.-
H.; Nilar, S.; Shaw, S.; Yao, N. 2004 WO 2004/030611; (b)
Wang, Z.; Wu, B.; Kuhen, K. L.; Bursulaya, B.; Nguyen,
T. N.; Nguyen, D. G.; He, Y. Bioorg. Med. Chem. Lett.
2006, 16, 4174; (c) De La Rosa, M.; Kim, H. W.; Gunic,
E.; Jenket, C.; Boyle, U.; Koh, Y.; Korboukh, I.; Allan,
M.; Zhang, W.; Chen, H.; Xu, W.; Nilar, S.; Yao, N.;
Hamatake, R.; Lang, S. A.; Hong, Z.; Zhang, Z.;
Girardet, J.-L. Bioorg. Med. Chem. Lett. 2006, 16, 4444;
(d) Zhang, Z.; Xu, W.; Koh, Y.-H.; Shim, J. H.; Girardet,
J.-L.; Yeh, L.-T.; Hamatake, R. K.; Hong, Z. Antimicrob.
Agents Chemother. 2007, 51, 429.
4. Turner, D.; Wainberg, M. A. AIDS Rev. 2006, 8,
17.
5. Blackard, J. T.; Cohen, D. E.; Mayer, K. H. Clin. Infect.
Dis. 2002, 34, 1108.
6. For reviews on emerging drugs, see: (a) Uckun, F. M.;
D’Cruz, O. J. Exp. Opin. Ther. Patents 2006, 16, 265; (b)
De Clercq, E. Exp. Opin. Emerg. Drugs 2005, 10,
241.
7. Castro, H. C.; Loureiro, N. I. V.; Pujol-Luz, M.; Souza,
A. M. T.; Albuquerque, M. G.; Santos, D. O.; Cabral, L.
M.; Frugulhetti, I. C.; Rodrigues, C. R. Curr. Med. Chem.
2006, 13, 313.
8. Boone, L. R. Curr. Opin. Invest. Drugs 2006, 7, 128.
9. IC50 values for WT and mutant RTs were obtained from a
scintillation proximity assay using poly rC/biotin-dG15
and H-dGTP at 37 °C.
10. Gallant, J. E. Top. HIV Med. 2005, 13, 138.
11. (a) Other groups have reported similar activity against the
HIV RT for compound 1: (a) Shaw-Reid, C.A.; Miller,
M.D.; Hazuda, D.J.; Ferrer, M.; Sur, S.M.; Summa, V.;
Lyle, T.A.; Kinzel, O.; Pescatore, G.; Muraglia, E.;
Orvieto, F.; Williams, P.D. 2005 WO 2005/115147; (b)
Muraglia, E.; Kinzel, O. D.; Laufer, R.; Miller, M. D.;
Moyer, G.; Munshi, V.; Orvieto, F.; Palumbi, M. C.;
Pescatore, G.; Rowley, M.; Williams, P. D.; Summa, V.
Bioorg. Med. Chem. Lett. 2006, 16, 2748.
15. Compound 3 had a t1/2 (HLM) of 5 min, whereas
compound 4 had a t1/2 (HLM) of 170 min.
16. Kelly, T. A.; McNeil, D. W. Tetrahedron Lett. 1994, 35,
9003.
17. For EC50 determinations, C8166 cells were acutely
infected (MOI 0.001) and incubated with inhibitors for 3
days at 37 °C. Viral replication was assessed by p24
ELISA of the culture supernatants.
18. t1/2 values for phase I oxidative metabolitic stability were
determined using rat liver microsomes at a concentration
of 2 lM for the compounds.
3
19. DeRoy, P.; Faucher, A.-M.; Gagnon, A.; Landry, S.;
Morin, S.; O’Meara, J.; Simoneau, B.; Thavonekham, B.;
Yoakim, C. 2005 WO 2005/118575.