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. 2011 Jan 11;2(3):224-9.
doi: 10.1021/ml1002647. eCollection 2011 Mar 10.

Inhibitors of HCV NS5A: From Iminothiazolidinones to Symmetrical Stilbenes

Jeffrey L Romine  1 , Denis R St Laurent  1 , John E Leet  2 , Scott W Martin  1 , Michael H Serrano-Wu  1 , Fukang Yang  1 , Min Gao  3 , Donald R O'Boyle 2nd  3 , Julie A Lemm  3 , Jin-Hua Sun  3 , Peter T Nower  3 , Xiaohua Stella Huang  4 , Milind S Deshpande  1 , Nicholas A Meanwell  1 , Lawrence B Snyder  1
Affiliations

Inhibitors of HCV NS5A: From Iminothiazolidinones to Symmetrical Stilbenes

Jeffrey L Romine et al. ACS Med Chem Lett. .

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.

Keywords: HCV NS5A inhibitor; iminothiazolidinone; stilbene.

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Figures

Scheme 1
Scheme 1. Synthetic Approach to Iminothiazolidinones Using Parallel Solution Phase Chemistry
Scheme 2
Scheme 2. Oxidative Rearrangement of the Iminothiazolidinones 2 and 18
Figure 1
Figure 1
Dimeric species identified in replicon assay media and pharmacophore hypothesis.
Scheme 3
Scheme 3. Radical Generation, Oxidation, and Trapping with Acetic Acid
See this image and copyright information in PMC

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