title: HCV NS5A replication complex inhibitors. Part 2: investigation of stilbene prolinamides.
abstract: In a previous disclosure,(1) we reported the dimerization of an iminothiazolidinone to form 1, a contributor to the observed inhibition of HCV genotype 1b replicon activity. The dimer was isolated via bioassay-guided fractionation experiments and shown to be a potent inhibitor of genotype 1b HCV replication for which resistance mapped to the NS5A protein. The elements responsible for governing HCV inhibitory activity were successfully captured in the structurally simplified stilbene prolinamide 2. We describe herein the early SAR and profiling associated with stilbene prolinamides that culminated in the identification of analogs with PK properties sufficient to warrant continued commitment to this chemotype. These studies represent the key initial steps toward the discovery of daclatasvir (BMS-790052), a compound that has demonstrated clinical proof-of-concept for inhibiting the NS5A replication complex in the treatment of HCV infection.
authors.affiliation: Department of Medicinal Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Denis R
authors.initials: DR
authors.lastname: St Laurent
authors.forename: Makonen
authors.initials: M
authors.lastname: Belema
authors.forename: Min
authors.initials: M
authors.lastname: Gao
authors.forename: Jason
authors.initials: J
authors.lastname: Goodrich
authors.forename: Ramesh
authors.initials: R
authors.lastname: Kakarla
authors.forename: Jay O
authors.initials: JO
authors.lastname: Knipe
authors.forename: Julie A
authors.initials: JA
authors.lastname: Lemm
authors.forename: Mengping
authors.initials: M
authors.lastname: Liu
authors.forename: Omar D
authors.initials: OD
authors.lastname: Lopez
authors.forename: Van N
authors.initials: VN
authors.lastname: Nguyen
authors.forename: Peter T
authors.initials: PT
authors.lastname: Nower
authors.forename: Donald
authors.initials: D
authors.lastname: O'Boyle
authors.forename: Yuping
authors.initials: Y
authors.lastname: Qiu
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Romine
authors.forename: Michael H
authors.initials: MH
authors.lastname: Serrano-Wu
authors.forename: Jin-Hua
authors.initials: JH
authors.lastname: Sun
authors.forename: Lourdes
authors.initials: L
authors.lastname: Valera
authors.forename: Fukang
authors.initials: F
authors.lastname: Yang
authors.forename: Xuejie
authors.initials: X
authors.lastname: Yang
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Snyder
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002219:Carbamates; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014633:Valine / Q000031:analogs & derivatives; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D011392:Proline; D011759:Pyrrolidines; D013267:Stilbenes; D014633:Valine; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C549273:daclatasvir; C056291:prolinamide