O

reported an inhibitor series that incorporates an aza-amino acyl fragment at the P1/P1' position (Table 2.2). The best compound identified contains a benzyl derivative. The choice of P1 side chain was important for providing specificity against other serine proteases. A four-carbon P1 side chain was found to be optimal (Compound (3)). NMR and SAR studies on this series of inhibitors demonstrated that they bind reversibly and non-covalently to the enzyme [116].

C-terminal acyl sulfonamide containing inhibitors

The uniqueness of the non-covalent product-based inhibitors containing C-terminal carboxylic acid prompted the exploration of bioisosteric

replacements of this critical group [117, 118]. Initial reports on hexa- and pentapeptide derivatives concluded that bioisosteric replacement of the C-terminal carboxylic acid of the product-based inhibitors with tetrazoles, and especially with acyl sulfonamide residues, produced product-based inhibitors up to 20-fold more potent than the corresponding carboxylates (Table 2.3). The aryl acyl sulfonamide group also allows for elongation into the P' region, as well as other structural modifications.

After the initial reports of the antiviral efficacy of BILN 2061 a large number of reports disclosing macrocyclic (Figure 2.10) [71, 119-124] and acyclic (Figure 2.11) [125-135] analogues have appeared. For some of these compounds an acyl sulfonamide has been also reported at the C-terminus.

P.W. WHITE, M. LLINAS-BRUNET AND M. BOS Table 2.2 NON-COVALENT AZAPEPTIDE INHIBITORS

COOH Ph

COOH Ph

(3)

Prime-side inhibitors

The IRBM group combined characteristic elements of the product-based inhibitors with decapeptide inhibitors to yield inhibitors binding solely to the prime side and active site of the protease [136]. Thus, the P1 a-carboxylate of the product-based inhibitors is now at the N-terminal cyclohexyl moiety, as illustrated in Figure 2.12. The peptidomimetic

Table 2.3 BIOISOSTERIC REPLACEMENTS OF THE C-TERMINAL CARBOXYLIC ACID

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