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Publication Abstract from PubMed

Starting with the indole-based C-3 pyridone lead HCV polymerase inhibitor 2, extensive SAR studies were performed at different positions of the indole core. The best C-5 groups were found to be compact and nonpolar moieties and that the C-6 attachments were not affecting potency. Limited N-1 benzyl-type substituent studies indicated that the best substitutions were fluoro or methyl groups at 2' or 5' positions of the benzyl group. To improve pharmacokinetic (PK) properties, acylsulfonamides were incorporated as acid isosteres at the C-2 position. Further optimization of the combination at N-1, C-2, C-5, and C-6 resulted in the identification of compound 56, which had an excellent potency in both NS5B enzyme (IC(50) = 0.008 muM) and cell-based replicon (EC(50) = 0.02 muM) assays and a good oral PK profile with area-under-the curve (AUC) of 14 and 8 muM.h in rats and dogs, respectively. X-ray structure of inhibitor 56 bound to the enzyme was also reported.

Structure-Activity Relationship (SAR) Development and Discovery of Potent Indole-Based Inhibitors of the Hepatitis C Virus (HCV) NS5B Polymerase.,Chen KX, Vibulbhan B, Yang W, Sannigrahi M, Velazquez F, Chan TY, Venkatraman S, Anilkumar GN, Zeng Q, Bennet F, Jiang Y, Lesburg CA, Duca J, Pinto P, Gavalas S, Huang Y, Wu W, Selyutin O, Agrawal S, Feld B, Huang HC, Li C, Cheng KC, Shih NY, Kozlowski JA, Rosenblum SB, Njoroge FG J Med Chem. 2012 Jan 26;55(2):754-65. Epub 2012 Jan 6. PMID:22148957^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.