1361147-40-1Relevant 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.
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.
