3410
R. B. Perni et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3406–3411
4. Reesink, H. A.; Zeuzem, S.; Weegink, C.; Forestier, N.;
van Vliet, A.; van de Wetering de Rooj, J.; McNair, L.;
Purdy, S.; Chu, H.-M. Hepatology 2005, 42, 69A.
5. Reesink, H. W.; Zeuzem, S.; Weegink, C. J.; Forestier, N.;
Van Vliet, A.; van de Wetering de Rooij, J.; McNair, L.;
Purdy, S.; Kaufffman, R.; Alam, J.; Jansen, P. L. M.
Gastroenterology 2006, 131, 997.
6. Lamarre, D.; Anderson, P. C.; Bailey, M.; Beaulieu, P.;
Bolger, G.; Bonneau, P.; Bos, M.; Camerson, D. R.;
Cartier, M.; Cordingly, M. G.; Faucher, A.-M.; Goud-
reau, N.; Kawai, S. H.; Kukolj, G.; Lagace’, L.; LaPlante,
S. R.; Narjes, H.; Poupart, M.-A.; Rancourt, J.; Sentjens,
R. E.; St George, R.; Simoneau, B.; Steinman, G.;
Thibeault, D.; Tzantrisous, Y. S.; Weldon, S. M.; Yong,
C.-L.; Llinas-Brunet, M. Nature 2003, 426, 186.
7. Zeuzem, S.; Sarrazin, C.; Rouzier, R.; Tarral, A.; Brion,
N.; Forestier, N.; Gupta, S.; Deckman, D.; Fellows, K.;
Hussain, M. D.; Cuttler, D. L.; Zhang, J. Hepatology
2005, 42, 233A.
8. Ingallinella, P.; Altamura, S.; Bianchi, E.; Taliani, M.;
Ingenito, R.; Cortese, R.; De Francesco, R.; Steinkuhler,
C.; Pessi, A. Biochemistry 1998, 37, 8906.
in mice, it was a relatively weak inhibitor of the protease
(Ki = 1.2 lM). Conversely, 11, a potent inhibitor in
enzymatic assay (Ki = 50 nM) as well as in the replicon
system (IC50 = 0.37 lM), showed relatively poor oral
bioavailability in mice. For orally bioavailable com-
pounds, the high lipophilicity resulted in higher liver
concentrations relative to plasma drug levels, a poten-
tially advantageous property given that the vast major-
ity, if not all, of the replicating HCV virions reside in
the liver.24 For example, 2 had an average liver concen-
tration that was approximately two-fold higher than the
average plasma concentration over 8 h. Similar results
were observed for 13 and 14 (approximately 1.5- and
four-fold, respectively). To observe the effect of incorpo-
rating a hydrogen bond-donating P4 cap onto the tela-
previr scaffold, compound 24,25 the P2 analogue of 12,
was prepared. Liver exposure for 24 was increased 20-
fold over that of 12. However, the plasma exposure
for 24 increased to a lesser degree than did the liver con-
centration. Relative to telaprevir, liver exposure was
modestly reduced (2·) but plasma exposure was reduced
approximately nine-fold.
9. Steinkuhler, C.; Basiol, G.; Brunetti, M.; Urbani, A.;
Koch, U.; Cortese, R.; Pessi, A.; De Francesco, R.
Biochemistry 1998, 37, 8899.
10. Cicero, D. O.; Barbato, G.; Koch, U.; Ingallinella, P.;
Bianchi, E.; Nardi, M. C.; Steinkuler, C.; Cortese, R.;
Matassa, V.; De Francesco, R.; Pessi, A.; Bazzo, R. J.
Mol. Biol. 1999, 289, 385.
11. Llinas-Brunet, M.; Bailey, M. D.; Fazal, G.; Goulet, S.;
Halmos, T.; LaPlante, S.; Muarice, R.; Poirer, M.;
Poupart, M.-A.; Thibeault, D.; Wernic, D.; Lamarre, D.
Bioorg. Med. Chem. Lett. 1998, 8, 1713.
N
O
H
N
N
O
N
N
H
H
H
H
N
N
O
O
O
O
24
12. Bennett, J. M.; Campbell, A. D.; Campbell, A. J.; Car, M.
G.; Dunsdon, R. M.; Greening, J. R.; Hurst, D. N.;
Jennings, N. S.; Jones, P. S.; Jordon, S.; Kay, P. B.;
O’Brien, M. A.; King-Underwood, J.; Raynham, T. M.;
Wilkinson, C. S.; Wilkinson, T. C. I.; Wilson, F. X.
Bioorg. Med. Chem. Lett. 2001, 11, 355.
13. Perni, R. B.; Britt, S. D.; Court, J. J.; Courtney, L. F.;
Deininger, D. D.; Farmer, L. J.; Gates, C. A.; Harbeson,
S. L.; Kim, J. L.; Landro, J. A.; Luong, Y.-P.; O’Malley,
E. T.; Pitlik, J.; Rao, B. G.; Schairer, W. C.; Thomson, J.
A.; Tung, R. D.; Van Drie, J. H.; Wei, Y. Bioorg. Med.
Chem. Lett. 2003, 13, 4059.
14. Yip, Y.; Victor, F.; Lamar, J.; Johnson, R. B.; Wang, Q.
M.; Glass, J. I.; Yumibe, N.; Wakulchik, M.; Munroe, J.;
Chen, S.-H. Bioorg. Med. Chem. Lett. 2004, 14, 5007.
15. Sun, D. X.; Liu, L.; Heinz, B.; Kolykhalov, A.; Lamar, J.;
Johnson, R. B.; Wang, Q. M.; Yip, Y.; Chen, S.-H.
Bioorg. Med. Chem. Lett. 2004, 14, 4333.
16. Perni, R. B.; Cottrell, K. M.; Court, J. J.; Farmer, L. J.;
Gates, C. A.; Lin, C.; Lin, K.; Luong, Y.-P.; Pitlik, J.;
Rao, G.; Schairer, W. C.; Wei, Y.; Van Drie, J. In 229th
National Meeting of the American Chemical Society San
Diego, CA, Abstract 327, March 2005.
The SAR of a series of inhibitors containing P4 cap-
ping groups with varying abilities to donate hydrogen
bonds to the NS3 binding groove has been described
in this report. Some of these compounds were potent
inhibitors of the HCV NS3Æ4A protease. The results
of enzymatic assays showed that incorporation of
groups that form strong hydrogen bonds with the
NS3Æ4A protein derive additional affinity. In general,
cellular activity tracked reasonably well with enzyme
binding affinity. The pharmacokinetic properties of a
subset of the inhibitor series demonstrate that the
inclusion of hydrogen bond donors adversely affected
oral bioavailability for this series. Careful balancing
of these competing properties (binding affinity vs. oral
bioavailability) is required to identify compounds with
the requisite drug-like properties.
17. Perni, R. B.; Chandorkar, G.; Chaturvedi, P.; Courtney,
L. F.; Decker, C. J.; Gates, C. A.; Harbeson; Kwong,
A. D.; Lin, C.; Luong, Y.-P.; Markland, W.; Rao, B.
G.; Thomson, J. A.; Tung, R. D. Hepatology 2003, 38,
624A.
18. Reesink, H. W.; Zeuzem, S.; Weegink, C. J.; Forestier, N.;
van Vliet, A.; van de Wetering de Rooij, J.; McNair, L.;
Purdy, S.; Chu, H.-M.; Jansen, P. L. M. In Digestive
Diseases Week, Chicago, IL, Abstract 527, May 2005.
19. Farmer, L. J.; Britt, S. D.; Cottrell, K. M.; Court, J. J.;
Courtney, L. F.; Deininger, D. D.; Gates, C. A.; Harbe-
son, S. L.; Lin, K.; Lin, C.; Luong, Y.-P.; Maxwell, J. M.;
Pitlik, J.; Rao, B. G.; Schiarer, W. C.; Thomson, J. A.;
References and notes
1. Afdhal, N. H. Seminars Liver Dis. 2004, 24, 3.
2. Fargion, S.; Fracanzani, A. L.; Valenti, L. J. Antimicrob.
Chemother. 2004, 53, 708.
3. Perni, R. B.; Almquist, S. J.; Byrn, R. A.; Chandorkar, G.;
Chaturvedi, P. R.; Courtney, L. F.; Decker, C. J.;
Dinehart, K.; Gates, C. A.; Harbeson, S. L.; Heiser, A.;
Kalkeri, G.; Kozikowski, E.; Lin, K.; Luong, Y.-P.; Rao,
B. G.; Taylor, W. P.; Thomson, J. A.; Tung, R. D.; Wei,
Y.; Kwong, A. D.; Lin, C. Antimicrob. Agents Chemother.
2006, 50, 899.