title: Tetracyclic indole inhibitors of hepatitis C virus NS5B-polymerase.
abstract: We report the evolutionary path from an open-chain series to conformationally constrained tetracyclic indole inhibitors of HCV NS5B-polymerase, where the C2 aromatic is tethered to the indole nitrogen. SAR studies led to the discovery of zwitterionic compounds endowed with good intrinsic enzyme affinity and cell-based potency, as well as superior DMPK profiles to their acyclic counterparts, and ultimately to the identification of a pre-clinical candidate with an excellent predicted human pharmacokinetic profile.
authors.affiliation: Department of Medicinal Chemistry, Istituto di Ricerche di Biologia Molecolare P. Angeletti S.p.A., Merck Research Laboratories Rome, 00040 Pomezia, Italy. ian_stansfield@merck.com
authors.forename: Ian
authors.initials: I
authors.lastname: Stansfield
authors.forename: Caterina
authors.initials: C
authors.lastname: Ercolani
authors.forename: Angela
authors.initials: A
authors.lastname: Mackay
authors.forename: Immacolata
authors.initials: I
authors.lastname: Conte
authors.forename: Marco
authors.initials: M
authors.lastname: Pompei
authors.forename: Uwe
authors.initials: U
authors.lastname: Koch
authors.forename: Nadia
authors.initials: N
authors.lastname: Gennari
authors.forename: Claudio
authors.initials: C
authors.lastname: Giuliano
authors.forename: Michael
authors.initials: M
authors.lastname: Rowley
authors.forename: Frank
authors.initials: F
authors.lastname: Narjes
mesh_terms: D000495:Allosteric Site; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D016174:Hepacivirus; D006801:Humans; D006868:Hydrolysis; D007211:Indoles / Q000737:chemistry; D008956:Models, Chemical; D009584:Nitrogen / Q000737:chemistry; D011487:Protein Conformation; D051381:Rats; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D009584:Nitrogen; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase