2061, whereas the primary resistance mutations for BILN 2061, at Asp-168, do not significantly affect the potency of VX-950 [91]. The crystal structure of the inhibitory complex shows only partial overlap with the protein regions covered by BILN 2061 providing an explanation for the activity of

VX-950 against NS3 mutants that are insensitive to BILN 2061, and vice versa [91].

Scientists at Bristol-Myers Squibb used the a-ketoamide functionality to extend binding to the prime side [147]. The glycine carboxylic acid (Compound (5), Table 2.5) was identified as the most effective extension. Modelling studies, coupled with SAR, suggested that there is either hydrogen bonding or a charge complex of the acid with Lys-136 and Arg-109.

The synthesis of aldehydes and ketoamides was performed on solid phase as well as in solution (Scheme 2.2). A semicarbazone linker (6) was employed for the assembly of the aldehydes on solid phase whereas the corresponding aminoalcohol was coupled in solution to the tripeptide and oxidized to the aldehyde, which produced epimeric mixtures [137]. For the synthesis of the ketoamides, hydroxyester THP resins were used as solid support ((7), Scheme 2.2) [138]. In solution the peptide bond was formed using an aminohydroxycarboxylic acid building block [138, 147]. Oxidation of the free hydroxyl group yielded the final inhibitors ((8), Scheme 2.2).

The pyrrolidine-5,5-Zrans-lactam ring system, developed by the Glaxo group as a serine trap for a number of proteases, was applied to the NS3 protease [148, 149] (Scheme 2.3). As shown by X-ray structure analysis, the serine hydroxyl attacks the lactam carbonyl, which is activated by ring strain as well as by the N-acyl group to form a hemiketal [150]. The challenge is to find compounds, which display reasonable chemical stability and consequently favorable in vivo pharmacokinetic properties and good biochemical potency. GW0014 (Scheme 2.3) was identified as such an inhibitor and was tested in the GBV-B infected marmoset, showing a three-log virus titer reduction in this surrogate animal model [81]. The ring system is synthetically accessible via acyliminium coupling to ketene acetals followed by ring closure with tBuMgCl (Scheme 2.3) [148, 151].

Boronic acid derivatives are known to inhibit serine proteases through the formation of a reversible tight B-O bond. Bristol-Myers Squibb published a series of peptidic [152] as well as peptidomimetic ( + )-pinanediol boronates [153, 154] targeting the NS3 protease (Scheme 2.4). The latter feature a bicyclic pyrimidone and pyrazinone core replacing the P2-P3 dipeptide. These heterocyclic scaffolds allow the formation of the necessary b-sheet hydrogen bonds between the carbonyl and NH of the ring system and the enzyme backbone, as well as extension into the S2 binding pocket. Inhibitors derived from these structural motifs, such as compound (9), display high enzymatic potency, but no replicon data are available.

The heterocyclic scaffolds are prepared from pyroglutamic acid [154, 155]. 1-aminoalkyl boronic acid pinanediol esters are readily available through a diastereoselective homologation with dichloromethyllithium, providing (S)-a-chloroboronic esters. Aminolysis of the chloride yielded

Scheme 2.2 Synthesis of peptidic covalent inhibitors.

^COOEt K2CO3 T tBuMgCl


^COOEt K2CO3 T tBuMgCl


Scheme 2.3 Synthesis of pyrrolidine-5,5-trans-lactams.

(R)-aminoboronic esters, which are coupled to the pentapeptides or to the bicyclic peptidomimetics (Scheme 2.4) [152].

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