Inhibitors of hepatitis C virus NS3·4A protease. Part 3: P2 proline variants

Inhibitors of Hepatitis C Virus NS3.4A Protease: P2 Proline Variants

“…Michael addition of (S-)-camphor imine glycine t-butyl ester anion [10] 23 to trisubstituted enoates 22a, 22b, and 22c provided The synthesis of tricyclic proline scaffold 29 shown in Scheme 3 started from a Diels-Alder reaction between pyroglutaminol 27 [11] and cyclopentadiene in toluene at 100°C to provide, after catalytic hydrogenation, tricyclic pyroglutaminol 28. The final tricyclic proline 29 was then prepared using the same methodology as previously reported [8]. The two diatereomeric carbomethoxy methanoprolines 30 and 31 were prepared as previously reported by Madalengoitia et al [12].…”

“…The major discernable trend in this SAR implies that larger groups are directed perpendicular to the proline C2-C3 bond, such as 9 and 12, were more tightly bound to the enzyme than small rings or those attached at the proline C-4. The final tetrapeptides 5-16 (Scheme 5) were assembled using the same methodology as reported in our previous paper [8].…”

“…Reduction of the lactam with borane-THF followed by hydrogenolysis provided prolines intermediate 32 and 33. The final methanoprolines 34 and 35 were prepared using the same methodology as previously reported [8].…”

“…2 K i = 0.42 µM) [7]. To address the size issue, we recently reported on a novel 3-alkyl proline based tetrapeptide inhibitor series [8] HCV infection has reached epidemic proportion worldwide and to date therapy options are limited and clinical results variable [1]. The inhibition of the hepatitis C virus NS3•4A protease has been an intense area of research such as 3 that retains significant binding potency despite their relatively smaller molecular size.…”

Discovery and Development of Telaprevir (Incivek™) – A Protease Inhibitor to Treat Hepatitis C Infection

“…Not surprisingly, these compounds displayed poor PK profiles giving low liver and plasma exposures upon single PO dose administration in mice. At this time, the P2 site was revisited to investigate proline substitution other than 4-hydroxyproline-based analogs [18]. Re-examination of the crystal structure of hydroxyproline-based inhibitor 7 led to the hypothesis that proline-based P2s bearing a 1-4 carbon substituent at the 3 position on the alpha face could result in displacement of a putative water molecule in the enzyme active site, thus leading to improved binding affinity.…”