title: Design, synthesis, and evaluation of oxygen-containing macrocyclic peptidomimetics as inhibitors of HCV NS3 protease.
abstract: HCV infection is considered a silent epidemic because most people infected do not develop acute symptoms. Instead, the disease progresses to a chronic state leading to cirrhosis and hepatocarcinoma. Novel therapies are needed to combat this major health threat. The HCV NS3 serine protease has been the target of continuous investigation because of its pivotal role in viral replication. Herein, we present the P1-P3 macrocyclization approach followed for identification of HCV NS3 inhibitors as potential backup candidates to our first generation drug candidate, Sch 503034 (1). Different P1-P3 linkers were investigated to identify novel macrocyclic scaffolds. SAR exploration of P3-caps in the macrocyclic cores allowed the identification of l-serine derived macrocycle 32 (Ki* = 3 nM, EC90 = 30 nM) and allo-threonine derived macrocycle 36 (Ki* = 3 nM, EC90 = 30 nM) as potent HCV NS3 protease inhibitors.
authors.affiliation: Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033-1300, USA. francisco.velazquez@spcorp.com
authors.forename: Francisco
authors.initials: F
authors.lastname: Velázquez
authors.forename: Srikanth
authors.initials: S
authors.lastname: Venkatraman
authors.forename: Melissa
authors.initials: M
authors.lastname: Blackman
authors.forename: Patrick
authors.initials: P
authors.lastname: Pinto
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bogen
authors.forename: Mousumi
authors.initials: M
authors.lastname: Sannigrahi
authors.forename: Kevin
authors.initials: K
authors.lastname: Chen
authors.forename: John
authors.initials: J
authors.lastname: Pichardo
authors.forename: Andrea
authors.initials: A
authors.lastname: Hart
authors.forename: Xiao
authors.initials: X
authors.lastname: Tong
authors.forename: Viyyoor
authors.initials: V
authors.lastname: Girijavallabhan
authors.forename: F George
authors.initials: FG
authors.lastname: Njoroge
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology; D015195:Drug Design; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D047028:Macrocyclic Compounds; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases