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substitution (60i) resulted in improved potency (EC50 = 7 nM),
however with loss of permeability in the Caco-2 assay
(Papp = 0.4 Â 10À6 cm/s). The corresponding pyridyl substitutions
of 60h, and in particular of 60g however resulted in decreased po-
tency (EC50 = 13 and 130 nM, respectively).
Based on the excellent potency and in vitro DMPK properties for
these quinazoline containing inhibitors four compounds were se-
lected for evaluation of their in vivo pharmacokinetic properties
in rats. This comprised examples from all three series, that is, the
cyclopentane series (51a), the 14-membered N-methyl proline
urea series (60a and 60c), as well as the 15-membered NH proline
urea series (67c) and the results are shown in Table 3.
The mean plasma levels, liver-to-plasma ratios together with
pharmacokinetic parameters were determined after a single intra-
venous and oral administration in male Sprague–Dawley rats. The
proline urea derivatives 60a, 60c, and 67c were all found to have
favorable liver-to-plasma ratios (32–100) after 6 h and were hence
well distributed to the liver. The cyclopentane derivative 51a did
however not reach detectable concentrations and the liver-to-plas-
ma ratio could thus not be determined. When comparing the two
compounds 51a (Cmax = 0.66 lM) and 60a (Cmax = 3.4 lM), the
mean maximum plasma concentrations (Cmax) were achieved after
2 h for the cyclopentane derivative and after 5 h for the proline
compound indicating a slower absorption for 60a but also a higher
Cmax and hence a larger area under the curve (AUC).
The 15-membered NH proline urea derivative 67c exhibited
three times higher clearance (1.6 L/h/kg), associated with a signif-
icantly lower Cmax (0.39 lM) and AUC (1.7 lM h) compared with
the two 14-membered N-methyl proline urea derivatives 60a and
60c.
Taken together, these in vivo PK results support further SAR
studies on quinazoline substituted P2 proline ureas of the 14-
membered macrocyclic ring series to access potent HCV protease
inhibitors displaying high oral bioavailability in combination with
high liver-to-plasma ratios.
11. Vendeville, S.; Nilsson, M.; de Kock, H.; Lin, T.-I.; Antonov, D.; Classon, B.;
Ayesa, S.; Ivanov, V.; Johansson, P.-O.; Kahnberg, P.; Eneroth, A.; Wikström, K.;
Vrang, L.; Edlund, M.; Lindström, S.; Van de Vreken, W.; McGowan, D.; Tahri,
A.; Hu, L.; Lenz, O.; Delouvroy, R.; Van Dooren, M.; Kindermans, N.; Surleraux,
D.; Wigerinck, P.; Rosenquist, Å.; Samuelsson, B.; Simmen, K.; Raboisson, P.
Bioorg. Med. Chem. Lett. 2008, 18, 6189.
12. Ashmore, J. W. US 4781750, 1988.
13. Schmidt, H.-W. Synthesis 1985, 8, 778.
14. Llinas-Brunet, M.; Bailey, M. D.; Cameron, D.; Faucher, A.-M.; Ghiro, E.;
Goudreau, N.; Halmos, T.; Poupart, M.-A.; Rancourt, J.; Tsantrizos, T. S.; Wernic,
D. M.; Simoneau, B. WO 2000/09543, 2000.
15. Connolly, D. J.; Lacey, P. M.; McCarthy, M.; Saunders, C. P.; Carroll, A.-M.;
Goddard, R.; Guiry, P. J. J. Org. Chem. 2004, 69, 6572.
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