1354331-07-9Relevant academic research and scientific papers
Structure-activity relationship (SAR) development and discovery of potent indole-based inhibitors of the Hepatitis C Virus (HCV) NS5B polymerase
Chen, Kevin X.,Vibulbhan, Bancha,Yang, Weiying,Sannigrahi, Mousumi,Velazquez, Francisco,Chan, Tin-Yau,Venkatraman, Srikanth,Anilkumar, Gopinadhan N.,Zeng, Qingbei,Bennet, Frank,Jiang, Yueheng,Lesburg, Charles A.,Duca, Jose,Pinto, Patrick,Gavalas, Stephen,Huang, Yuhua,Wu, Wanli,Selyutin, Oleg,Agrawal, Sony,Feld, Boris,Huang, Hsueh-Cheng,Li, Cheng,Cheng, Kuo-Chi,Shih, Neng-Yang,Kozlowski, Joseph A.,Rosenblum, Stuart B.,Njoroge, F. George
, p. 754 - 765 (2012/03/11)
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 (IC50 = 0.008 μM) and cell-based replicon (EC50 = 0.02 μM) assays and a good oral PK profile with area-under-the curve (AUC) of 14 and 8 μM?h in rats and dogs, respectively. X-ray structure of inhibitor 56 bound to the enzyme was also reported.
A novel class of highly potent irreversible hepatitis C virus NS5B polymerase inhibitors
Chen, Kevin X.,Lesburg, Charles A.,Vibulbhan, Bancha,Yang, Weiying,Chan, Tin-Yau,Venkatraman, Srikanth,Velazquez, Francisco,Zeng, Qingbei,Bennett, Frank,Anilkumar, Gopinadhan N.,Duca, Jose,Jiang, Yueheng,Pinto, Patrick,Wang, Li,Huang, Yuhua,Selyutin, Oleg,Gavalas, Stephen,Pu, Haiyan,Agrawal, Sony,Feld, Boris,Huang, Hsueh-Cheng,Li, Cheng,Cheng, Kuo-Chi,Shih, Neng-Yang,Kozlowski, Joseph A.,Rosenblum, Stuart B.,Njoroge, F. George
, p. 2089 - 2101 (2012/05/04)
Starting from indole-based C-3 pyridone HCV NS5B polymerase inhibitor 2, structure-activity relationship (SAR) investigations of the indole N-1 benzyl moiety were performed. This study led to the discovery of irreversible inhibitors with p-fluoro-sulfone- or p-fluoro-nitro-substituted N-1 benzyl groups which achieved breakthrough replicon assay potency (EC50 = 1 nM). The formation of a covalent bond with adjacent cysteine-366 thiol was was proved by mass spectroscopy and X-ray crystal structure studies. The C-5 ethyl C-2 carboxylic acid derivative 47 had an excellent oral area-under-the-curve (AUC) of 18 μM?h (10 mg/kg). Its oral exposure in monkeys and dogs was also very good. The NMR ALARM assay, mass spectroscopy experiments, in vitro counter screening, and toxicology assays demonstrated that the covalent bond formation between compound 47 and the protein was highly selective and specific. The overall excellent profile of 47 made it an interesting candidate for further investigation.
