55565-28-1Relevant academic research and scientific papers
Synthesis and biological evaluation of novel 10-substituted-7- Ethyl-10-hydroxycamptothecin (SN-38) prodrugs
Mo, Zhou,Liu, Meixia,He, Xinhua,Yao, Yishan,Fan, Shiyong,Zhang, Ping,Shi, Weiguo,Zhong, Bohua,Yu, Hong,Wu, Di
, p. 19718 - 19731 (2014)
In an attempt to improve the antitumor activity and reduce the side effects of irinotecan (2), novel prodrugs of SN-38 ( 3) were prepared by conjugating amino acids or dipeptides to the 10-hydroxyl group of SN-38 via a carbamate linkage. The synthesized compounds completely generated SN-38 in pH 7.4 buffer or in human plasma, while remaining stable under acidic conditions. All prodrug compounds demonstrated much greater in vitro antitumor activities against HeLa cells and SGC-7901 cells than irinotecan. The most active compounds, 5h, 7c, 7d, and 7f, exhibited IC50 values that were 1000 times lower against HeLa cells and 30 times lower against SGC-7901 cells than those of irinotecan, and the inhibitory activities of these prodrugs against acetylcholinesterase (AchE) were significantly reduced, with IC50 values more than 6.8 times greater than that of irinotecan. In addition, compound 5e exhibited the same level of tumor growth inhibitory activity as irinotecan (CPT-11) in a human colon xenograft model in vivo.
Toward the back-up of Boceprevir (SCH 503034): Discovery of new extended P4-capped ketoamide inhibitors of hepatitis C virus NS3 serine protease with improved potency and pharmacokinetic profiles
Bogen, Stéphane L.,Pan, Weidong,Ruan, Sumei,Nair, Latha G.,Arasappan, Ashok,Bennett, Frank,Chen, Kevin X.,Jao, Edwin,Venkatraman, Srikanth,Vibulbhan, Bancha,Liu, Rong,Cheng, Kuo-Chi,Guo, Zhuyan,Tong, Xiao,Saksena, Anil K.,Girijavallabhan, Viyyoor,Njoroge, F. George
scheme or table, p. 3679 - 3688 (2010/04/05)
Hepatitis C is the most prevalent liver disease. Viral hepatitis C (HCV), a small (+)-RNA virus, infects chronically an estimated 300 million people worldwide. Results of Phase I clinical studies with our first generation HCV inhibitor Boceprevir, SCH 503034 (1), presented at the 56th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) were encouraging, and thus, additional human clinical studies are underway. In view of the positive data from our first generation compound, further work aimed at optimizing its overall profile was undertaken. Herein, we report that extension of our earlier inhibitor to the P4 pocket and optimization of the P1′ capping led to the discovery of new ketoamide inhibitors of the HCV NS3 serine protease with improved in vitro potency. In addition to being potent inhibitors of HCV subgenomic RNA replication, some of the new P4-capped inhibitors were also found to have improved PK profile.
