1354330-79-2Relevant academic research and scientific papers
Discovery of SCH 900188: A potent hepatitis C virus NS5B polymerase inhibitor prodrug as a development candidate
Chen, Kevin X.,Venkatraman, Srikanth,Anilkumar, Gopinadhan N.,Zeng, Qingbei,Lesburg, Charles A.,Vibulbhan, Bancha,Velazquez, Francisco,Chan, Tin-Yau,Bennet, Frank,Jiang, Yueheng,Pinto, Patrick,Huang, Yuhua,Selyutin, Oleg,Agrawal, Sony,Huang, Hsueh-Cheng,Li, Cheng,Cheng, Kuo-Chi,Shih, Neng-Yang,Kozlowski, Joseph A.,Rosenblum, Stuart B.,Njoroge, F. George
supporting information, p. 244 - 248 (2014/04/03)
Starting from indole-based hepatitis C virus (HCV) NS5B polymerase inhibitor lead compound 1, structure modifications were performed at multiple indole substituents to improve potency and pharmacokinetic (PK) properties. Bicyclic quinazolinone was found to be the best substituent at indole nitrogen, while 4,5-furanylindole was identified as the best core. Compound 11 demonstrated excellent potency. Its C2 N,N-dimethylaminoethyl ester prodrug 12 (SCH 900188) demonstrated significant improvement in PK and was selected as the development candidate.
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.
