title: HCV NS5A replication complex inhibitors. Part 3: discovery of potent analogs with distinct core topologies.
abstract: In a recent disclosure, we described the discovery of dimeric, prolinamide-based NS5A replication complex inhibitors exhibiting excellent potency towards an HCV genotype 1b replicon. That disclosure dealt with the SAR exploration of the peripheral region of our lead chemotype, and herein is described the SAR uncovered from a complementary effort that focused on the central core region. From this effort, the contribution of the core region to the overall topology of the pharmacophore, primarily vector orientation and planarity, was determined, with a set of analogs exhibiting <10 nM EC(50) in a genotype 1b replicon assay.
authors.affiliation: Department of Medicinal Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA. omar.lopez@bms.com
authors.forename: Omar D
authors.initials: OD
authors.lastname: Lopez
authors.forename: Van N
authors.initials: VN
authors.lastname: Nguyen
authors.forename: Denis R
authors.initials: DR
authors.lastname: St Laurent
authors.forename: Makonen
authors.initials: M
authors.lastname: Belema
authors.forename: Michael H
authors.initials: MH
authors.lastname: Serrano-Wu
authors.forename: Jason T
authors.initials: JT
authors.lastname: Goodrich
authors.forename: Fukang
authors.initials: F
authors.lastname: Yang
authors.forename: Yuping
authors.initials: Y
authors.lastname: Qiu
authors.forename: Amy S
authors.initials: AS
authors.lastname: Ripka
authors.forename: Peter T
authors.initials: PT
authors.lastname: Nower
authors.forename: Lourdes
authors.initials: L
authors.lastname: Valera
authors.forename: Mengping
authors.initials: M
authors.lastname: Liu
authors.forename: Donald R
authors.initials: DR
authors.lastname: O'Boyle
authors.forename: Jin-Hua
authors.initials: JH
authors.lastname: Sun
authors.forename: Robert A
authors.initials: RA
authors.lastname: Fridell
authors.forename: Julie A
authors.initials: JA
authors.lastname: Lemm
authors.forename: Min
authors.initials: M
authors.lastname: Gao
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Good
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 / Q000737:chemistry* / Q000494:pharmacology; D002219:Carbamates; D016174:Hepacivirus / Q000187:drug effects; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011392:Proline / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines; D013329:Structure-Activity Relationship; D014633:Valine / Q000031:analogs & derivatives; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D011392:Proline; D011759:Pyrrolidines; D014633:Valine; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C549273:daclatasvir; C056291:prolinamide