title: Syntheses and initial evaluation of a series of indolo-fused heterocyclic inhibitors of the polymerase enzyme (NS5B) of the hepatitis C virus.
abstract: Herein, we present initial SAR studies on a series of bridged 2-arylindole-based NS5B inhibitors. The introduction of bridging elements between the indole N1 and the ortho-position of the 2-aryl moiety resulted in conformationally constrained heterocycles that possess multiple additional vectors for further exploration. The binding mode and pharmacokinetic (PK) properties of select examples, including: 13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[2,1-d][1,4]benzodiazepine-10-carboxylic acid (7) (IC(50)=0.07 μM, %F=18), are reported.
authors.affiliation: Discovery Chemistry and Candidate Optimization, Bristol Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA. xiaofan.zheng@bms.com
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Zheng
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Hudyma
authors.forename: Scott W
authors.initials: SW
authors.lastname: Martin
authors.forename: Carl
authors.initials: C
authors.lastname: Bergstrom
authors.forename: Min
authors.initials: M
authors.lastname: Ding
authors.forename: Feng
authors.initials: F
authors.lastname: He
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Romine
authors.forename: Michael A
authors.initials: MA
authors.lastname: Poss
authors.forename: John F
authors.initials: JF
authors.lastname: Kadow
authors.forename: Chong-Hwan
authors.initials: CH
authors.lastname: Chang
authors.forename: John
authors.initials: J
authors.lastname: Wan
authors.forename: Mark R
authors.initials: MR
authors.lastname: Witmer
authors.forename: Paul
authors.initials: P
authors.lastname: Morin
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Camac
authors.forename: Steven
authors.initials: S
authors.lastname: Sheriff
authors.forename: Brett R
authors.initials: BR
authors.lastname: Beno
authors.forename: Karen L
authors.initials: KL
authors.lastname: Rigat
authors.forename: Ying-Kai
authors.initials: YK
authors.lastname: Wang
authors.forename: Robert
authors.initials: R
authors.lastname: Fridell
authors.forename: Julie
authors.initials: J
authors.lastname: Lemm
authors.forename: Dike
authors.initials: D
authors.lastname: Qiu
authors.forename: Mengping
authors.initials: M
authors.lastname: Liu
authors.forename: Stacey
authors.initials: S
authors.lastname: Voss
authors.forename: Lenore
authors.initials: L
authors.lastname: Pelosi
authors.forename: Susan B
authors.initials: SB
authors.lastname: Roberts
authors.forename: Min
authors.initials: M
authors.lastname: Gao
authors.forename: Jay
authors.initials: J
authors.lastname: Knipe
authors.forename: Robert G
authors.initials: RG
authors.lastname: Gentles
mesh_terms: D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects*; D016174:Hepacivirus / Q000201:enzymology*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D006571:Heterocyclic Compounds; D007211:Indoles; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase