Bioorganic & Medicinal Chemistry Letters 2012-10-01

HCV NS5A replication complex inhibitors. Part 2: investigation of stilbene prolinamides.

Denis R St Laurent, Makonen Belema, Min Gao, Jason Goodrich, Ramesh Kakarla, Jay O Knipe, Julie A Lemm, Mengping Liu, Omar D Lopez, Van N Nguyen, Peter T Nower, Donald O'Boyle, Yuping Qiu, Jeffrey L Romine, Michael H Serrano-Wu, Jin-Hua Sun, Lourdes Valera, Fukang Yang, Xuejie Yang, Nicholas A Meanwell, Lawrence B Snyder

Index: Bioorg. Med. Chem. Lett. 22(19) , 6063-6, (2012)

Full Text: HTML

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.Copyright © 2012 Elsevier Ltd. All rights reserved.