Novel P2-P4 macrocyclic inhibitors of HCV NS3/4A protease by P3 succinamide fragment depeptidization strategy.
Hepatitis C represents a serious worldwide health-care problem. Recently, we have disclosed a novel class of P2-P4 macrocyclic inhibitors of NS3/4A protease containing a carbamate functionality as capping group at the P3 N-terminus. Herein we report our work aimed at further depeptidizing the P3 region by replacement of the urethane function with a succinamide motif. This peptidomimetic approach has led to the discovery of novel P2-P4 macrocyclic inhibitors of HCV NS3/4A protease with sub-nanomolar enzyme affinities. In addition to being potent inhibitors of HCV subgenomic replication, optimized analogues within this series have also presented attractive PK properties and showed promising liver levels in rat following oral administration.
Pompei
Marco
M
IRBM, Rome, Italy. marco.pompei@gmail.com
Di Francesco
Maria Emilia
ME
Pesci
Silvia
S
Koch
Uwe
U
Vignetti
Sue Ellen
SE
Veneziano
Maria
M
Pace
Paola
P
Summa
Vincenzo
V
D000284:Administration, Oral; D000577:Amides / Q000737:chemistry; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001665:Binding Sites; D002460:Cell Line; D003198:Computer Simulation; D003521:Cyclopropanes; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics; D054833:Isoindoles; D047029:Lactams, Macrocyclic; D007930:Leucine / Q000031:analogs & derivatives; D011392:Proline / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013386:Succinates; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000577:Amides; D000998:Antiviral Agents; D003521:Cyclopropanes; D007211:Indoles; D054833:Isoindoles; D047029:Lactams, Macrocyclic; D007930:Leucine; D011392:Proline; D011480:Protease Inhibitors; D013386:Succinates; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C540393:vaniprevir; C011116:succinamide