title: Discovery of (7R)-14-cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl) amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid (MK-3281), a potent and orally bioavailable finger-loop inhibitor of the hepatitis C virus NS5B polymerase.
abstract: Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral genome and has been a prime target for drug discovery efforts. Here, we report on the further development of tetracyclic indole inhibitors, binding to an allosteric site on the thumb domain. Structure-activity relationship (SAR) studies around an indolo-benzoxazocine scaffold led to the identification of compound 33 (MK-3281), an inhibitor with good potency in the HCV subgenomic replication assay and attractive molecular properties suitable for a clinical candidate. The compound caused a consistent decrease in viremia in vivo using the chimeric mouse model of HCV infection.
authors.affiliation: Istituto Di Ricerche Di Biologia Molecolare, P. Angeletti SpA (Merck Research Laboratories, Rome), Pomezia, Italy. Frank.Narjes@astrazeneca.com
authors.forename: Frank
authors.initials: F
authors.lastname: Narjes
authors.forename: Benedetta
authors.initials: B
authors.lastname: Crescenzi
authors.forename: Marco
authors.initials: M
authors.lastname: Ferrara
authors.forename: Jörg
authors.initials: J
authors.lastname: Habermann
authors.forename: Stefania
authors.initials: S
authors.lastname: Colarusso
authors.forename: Maria del Rosario Rico
authors.initials: Mdel R
authors.lastname: Ferreira
authors.forename: Ian
authors.initials: I
authors.lastname: Stansfield
authors.forename: Angela Claire
authors.initials: AC
authors.lastname: Mackay
authors.forename: Immacolata
authors.initials: I
authors.lastname: Conte
authors.forename: Caterina
authors.initials: C
authors.lastname: Ercolani
authors.forename: Simone
authors.initials: S
authors.lastname: Zaramella
authors.forename: Maria-Cecilia
authors.initials: MC
authors.lastname: Palumbi
authors.forename: Philip
authors.initials: P
authors.lastname: Meuleman
authors.forename: Geert
authors.initials: G
authors.lastname: Leroux-Roels
authors.forename: Claudio
authors.initials: C
authors.lastname: Giuliano
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Fiore
authors.forename: Stefania
authors.initials: S
authors.lastname: Di Marco
authors.forename: Paola
authors.initials: P
authors.lastname: Baiocco
authors.forename: Uwe
authors.initials: U
authors.lastname: Koch
authors.forename: Giovanni
authors.initials: G
authors.lastname: Migliaccio
authors.forename: Sergio
authors.initials: S
authors.lastname: Altamura
authors.forename: Ralph
authors.initials: R
authors.lastname: Laufer
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Francesco
authors.forename: Michael
authors.initials: M
authors.lastname: Rowley
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004285:Dogs; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008253:Macaca mulatta; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D008958:Models, Molecular; D015394:Molecular Structure; D010079:Oxazocines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014766:Viremia / Q000188:drug therapy / Q000821:virology; D014779:Virus Replication / Q000187:drug effects
chemical_list: C562245:14-cyclohexyl-7-((2-(dimethylamino)ethyl)(methyl)amino)-7,8-dihydro-6H-indolo(1,2-e)(1,5)benzoxazocine-11-carboxylic acid; D000998:Antiviral Agents; D007211:Indoles; D010079:Oxazocines; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase