title: Novel P2-P4 macrocyclic inhibitors of HCV NS3/4A protease by P3 succinamide fragment depeptidization strategy.
abstract: 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.
authors.affiliation: IRBM, Rome, Italy. marco.pompei@gmail.com
authors.forename: Marco
authors.initials: M
authors.lastname: Pompei
authors.forename: Maria Emilia
authors.initials: ME
authors.lastname: Di Francesco
authors.forename: Silvia
authors.initials: S
authors.lastname: Pesci
authors.forename: Uwe
authors.initials: U
authors.lastname: Koch
authors.forename: Sue Ellen
authors.initials: SE
authors.lastname: Vignetti
authors.forename: Maria
authors.initials: M
authors.lastname: Veneziano
authors.forename: Paola
authors.initials: P
authors.lastname: Pace
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Summa
mesh_terms: 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
chemical_list: 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