title: Inhibitors of HCV NS5A: From Iminothiazolidinones to Symmetrical Stilbenes.
abstract: The iminothiazolidinone BMS-858 (2) was identified as a specific inhibitor of HCV replication in a genotype 1b replicon assay via a high-throughput screening campaign. A more potent analogue, BMS-824 (18), was used in resistance mapping studies, which revealed that inhibitory activity was related to disrupting the function of the HCV nonstructural protein 5A. Despite the development of coherent and interpretable SAR, it was subsequently discovered that in DMSO 18 underwent an oxidation and structural rearrangement to afford the thiohydantoin 47, a compound with reduced HCV inhibitory activity. However, HPLC bioassay fractionation studies performed after incubation of 18 in assay media led to the identification of fractions containing a dimeric species 48 that exhibited potent antiviral activity. Excision of the key elements hypothesized to be responsible for antiviral activity based on SAR observations reduced 48 to a simplified, symmetrical, pharmacophore realized most effectively with the stilbene 55, a compound that demonstrated potent inhibition of HCV in a genotype 1b replicon with an EC50 = 86 pM.
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Romine
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Denis R
authors.initials: DR
authors.lastname: St Laurent
authors.affiliation: Synthesis & Analysis Technology Team, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: John E
authors.initials: JE
authors.lastname: Leet
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Martin
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Serrano-Wu
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Fukang
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Virology, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Min
authors.initials: M
authors.lastname: Gao
authors.affiliation: Department of Virology, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Donald R
authors.initials: DR
authors.lastname: O'Boyle
authors.affiliation: Department of Virology, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Lemm
authors.affiliation: Department of Virology, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Jin-Hua
authors.initials: JH
authors.lastname: Sun
authors.affiliation: Department of Virology, B ristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Nower
authors.affiliation: Discovery Analytical Sciences, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Xiaohua Stella
authors.initials: XS
authors.lastname: Huang
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Milind S
authors.initials: MS
authors.lastname: Deshpande
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Snyder
keywords: HCV NS5A inhibitor; iminothiazolidinone; stilbene