P1 and P3 optimization of novel bicycloproline P2 bearing tetrapeptidyl α-ketoamide based HCV protease inhibitors

Design, synthesis, and Gaussia luciferase Assay of triorganotin(IV)-based HCV inhibitors

“…Derivatives containing a-ketoamide electrophilic trap have been reported in the literature to be potent inhibitors of HCV NS3 serine protease (Victor et al, 2004), while diketo groups interact directly with Mg ions present in the enzyme active site of HCV NS5B polymerase (De Francesco et al, 2003) to stop the replication of HCV.…”

P1 and P1; Optimization of [3,4]-Bicycloproline P2 Incorporated Tetrapeptidyl α-Ketoamide Based HCV Protease Inhibitors

“…To our satisfaction, many members of such tetrapeptidyl α-ketoamide based inhibitors (e.g., I and II as shown in Fig. 1) demonstrated excellent overall inhibitor profiles including enzyme inhibitory potency, enzyme selectivity, cell-based activity, and adequate liver drug exposure [9,10]. Encouraged by these promising results, we decided to optimize P1 binding via incorporation of (S)-chirality at that…”

“…In the same vein, chemists from Eli Lilly focused their efforts on the design and systematic optimizations (P2 through P4) of a novel class of bicycloproline P2 bearing α-ketoamides as HCV protease inhibitors [8]. Towards this end, a number of recent papers from this institution detailed the discovery of various P2 bicycloproline incorporated α-ketoamide based NS3-4A inhibitors such as I [9], II [10], and III [11]. To our satisfaction, many members of such tetrapeptidyl α-ketoamide based inhibitors (e.g., I and II as shown in Fig.…”

α-Ketoamino acid ester derivatives as promising MAO inhibitors

“…[15][16][17][18] In parallel, their application in medicinal chemistry has fueled the development of several synthetic methods. [19][20][21][22][23][24][25][26][27][28][29][30] The synthesis of an a-ketoamide fragment could be achieved by the ring opening of N-acetylisatin 1 by attacking of an amine at C2-carbonyl group of N-acetylisatin.…”