The identification of α-ketoamides as potent inhibitors of hepatitis c virus nS3-4a proteinase

Atom-Economical Synthesis of the N(10)−C(17) Fragment of Cyclotheonamides via a Novel Passerini Reaction−Deprotection−Acyl Migration Strategy1

“…Such covalent inhibitors generally exhibit potent in vitro enzyme inhibitory activity, with sub-nanomolar equilibrium inhibitor constants ( K i ) being typical of representative members − …”

“…They were prepared by multistep homologation−hydrolysis approaches from arginine or ornithine precursors via cyanohydrin 10c,d (6−11 steps), orthothioformate, 10a,e (7−8 steps) or furyllithium addition−oxidation 10b (5 steps) protocols. Our interest in the design and synthesis of novel classes of α-ketoamides as small molecule inhibitors of serine proteases, including prolyl endopeptidase, thrombin, factor Xa, 3a, urokinase, and NS3A hepatitis C protease, led us to investigate multiple-component reaction-based (MCR) approaches to α-hydroxy- β -aminocarboxylic acid and amide derivatives. These versatile, stable intermediates readily undergo oxidation to ketoamide targets.…”

Design and Synthesis of Depeptidized Macrocyclic Inhibitors of Hepatitis C NS3-4A Protease Using Structure-Based Drug Design

“…The hydrolytic cycle is completed by the collapse of the tetrahedral intermediate followed by nucelophilic attack of water to hydrolyze the acylserine ester. A suitably placed electrophilic trap such as trifluoromethyl ketones, tricarbonyls, or ketoamides in inhibitors could reversibly trap serine by the formation of a tetrahedral adduct, thus inhibiting the enzyme catalytic cycle . This strategy has been well-explored and used for the identification of various serine protease inhibitors.…”

Peptide Inhibitors of Hepatitis C Virus NS3 Protease

“…The efficacy of IFN-α alone is poor; less that 50% of patients respond to treatment and an important proportion of them relapse after IFN-α withdrawal Introduction (Camps et al, 1994). Thus, the following types of inhibitors have been described: compounds derived from thiazolidine (Sudo et al, 1997), acetylated peptides derived from the NS5A/5B region (Llinas-Brunet et al, 1998), aldehyde and boric acid modified peptides derived from NS4A/4B (Attwood et al, 1999), ketoamide-modified peptides from the NS4A/B (Bennett et al, 2001), glycine α-ketoamide derived compounds (Han et al, 2003), halogenated benzanilide type compounds (Kakiuchi et al, 1998), 3-amino bicyclic pyrazinones (Zhang et al, 2003) and bicyclic pyrimidinone-based compounds (Glunz et al, 2003). Although these combinations increase efficacy, an important proportion of patients fail to respond.…”

“…This finding has prompted several groups to develop inhibitors of HCV protease NS3. Thus, the following types of inhibitors have been described: compounds derived from thiazolidine (Sudo et al, 1997), acetylated peptides derived from the NS5A/5B region (Llinas-Brunet et al, 1998), aldehyde and boric acid modified peptides derived from NS4A/4B (Attwood et al, 1999), ketoamide-modified peptides from the NS4A/B (Bennett et al, 2001), glycine α-ketoamide derived compounds (Han et al, 2003), halogenated benzanilide type compounds (Kakiuchi et al, 1998), 3-amino bicyclic pyrazinones (Zhang et al, 2003) and bicyclic pyrimidinone-based compounds (Glunz et al, 2003). Among the most active inhibitors of NS3 are those reported by Ingalinella et al (Ingallinella et al, 1998), who derived peptidomimetics from the regions NS4A/4B and NS3/NS4A (Ingallinella et al, 2000) respectively.…”