Optimization of thienopyrrole-based finger-loop inhibitors of the hepatitis C virus NS5B polymerase.
Infections caused by the hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The NS5B polymerase of HCV is responsible for the replication of viral RNA and has been a prime target in the search for novel treatment options. We had discovered allosteric finger-loop inhibitors based on a thieno[3,2-b]pyrrole scaffold as an alternative to the related indole inhibitors. Optimization of the thienopyrrole series led to several N-acetamides with submicromolar potency in the cell-based replicon assay, but they lacked oral bioavailability in rats. By linking the N4-position to the ortho-position of the C5-aryl group, we were able to identify the tetracyclic thienopyrrole 40, which displayed a favorable pharmacokinetic profile in rats and dogs and is equipotent with recently disclosed finger-loop inhibitors based on an indole scaffold.
Martin Hernando
Jose Ignacio
JI
Department of Medicinal Chemistry, Istituto di Ricerche di Biologia Molecolare P. Angeletti S.p.A. Merck Sharp & Dohme Research Laboratories Rome, Via Pontina km 30,600, 00040 Pomezia (Italy).
Ontoria
Jesus Maria
JM
Malancona
Savina
S
Attenni
Barbara
B
Fiore
Fabrizio
F
Bonelli
Fabio
F
Koch
Uwe
U
Di Marco
Stefania
S
Colarusso
Stefania
S
Ponzi
Simona
S
Gennari
Nadia
N
Vignetti
Sue Ellen
SE
Del Rosario Rico Ferreira
Maria
M
Habermann
Jörg
J
Rowley
Michael
M
Narjes
Frank
F
D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001392:Azocines / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D011487:Protein Conformation; D011758:Pyrroles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D001392:Azocines; D004791:Enzyme Inhibitors; D011758:Pyrroles; D017361:Viral Nonstructural Proteins; C545679:13-cyclohexyl-6-(-1-isopropylpyrrolidin-3-yl)-5,6,7,8-tetrahydrothieno(2,3-4,5)pyrrolo(2,1-a)(2,5)benzodiazocine-11-carboxylic acid; C521801:thienopyrrole; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase