S1

Fig. 2.6 X-ray structure of Compound (1) bound to the NS3 protease. Residues of the enzyme that are in contact with the inhibitor are highlighted.

shows that the inhibitor binds in close proximity to the catalytic residues and at the interface between the N- and C-terminal subdomains (Figure 2.6). Overall, the complex can be characterized as a surface interaction with only a single, relatively shallow pocket at S1. The complex structure suggested extensive hydrogen bonding between the C-terminal carboxylate and the oxyanion hole, consisting of the amide NH's of Ser-139, Ser-138, and Gly-137. The carboxylate also appeared to hydrogen bond to the eH of His-57, whereas the side-chain of the catalytic residue Ser-139 rotated away from the P1 carboxylate (Figure 2.6) [42].

Compound (1) suffered from an unfavorable pharmacokinetic profile when studied in rats. It is cleared very rapidly from rat plasma (half-life, tj=2 = 0.4 h) and is poorly bioavailable (F = 2%), as reflected by the low plasma concentration (area under the plasma concentration-time curve, AUC0_N = 0.2 mMh) following a single oral dose of 25mg/kg in rats [42]. The main challenge was to further optimize this series to obtain NS3 protease inhibitors with low-nanomolar cell-based potency (EC50< 10 nM) and with an adequate pharmacokinetic profile for oral absorption.

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