329314-68-3Relevant articles and documents
Discovery of potent 2,4-difluoro-linker poly(ADPribose) polymerase 1 inhibitors with enhanced water solubility and in vivo anticancer efficacy
Chen, Wen-Hua,Song, Shan-Shan,Qi, Ming-Hui,Huan, Xia-Juan,Wang, Ying-Qing,Jiang, Hualiang,Ding, Jian,Ren, Guo-Bin,Miao, Ze-Hong,Li, Jian
, p. 1521 - 1532 (2017)
Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially in breast and ovarian cancers; tumor cells that are deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, we identified a series of 2,4-difluorophenyl-linker analogs (15-55) derived from olaparib as novel PARP1 inhibitors. Four potent analogs 17, 43, 47, and 50 (IC50=2.2-4.4 nmol/L) effectively inhibited the proliferation of Chinese hamster lung fibroblast V-C8 cells (IC50=3.2-37.6 nmol/L) in vitro, and showed specificity toward BRCA-deficient cells (SI=40-510). The corresponding hydrochloride salts 56 and 57 (based on 43 and 47) were highly water soluble in pH=1.0 buffered salt solutions (1628.2 μg/mL, 2652.5 μg/mL). In a BRCA1-mutated xenograft model, oral administration of compound 56 (30 m?kg-1d-1, for 21 d) exhibited more prominent tumor growth inhibition (96.6%) compared with the same dose of olaparib (56.3%); in a BRCA2-mutated xenograft model, oral administration of analog 43 (10 m?kg-1d-1, for 28 d) significantly inhibited tumor growth (69.0%) and had no negative effects on the body weights. Additionally, compound 56 exhibited good oral bioavailability (F=32.2%), similar to that of olaparib (F=45.4%). Furthermore, the free base 43 of the hydrochloride salt 56 exhibited minimal hERG inhibition activity (IC50=6.64 μmol/L). Collectively, these data demonstrate that compound 56 may be an excellent drug candidate for the treatment of cancer, particularly BRCA-deficient tumors.
Optimization of potency and pharmacokinetics of tricyclic indole derived inhibitors of HCV NS5B polymerase. Identification of ester prodrugs with improved oral pharmacokinetics
Venkatraman, Srikanth,Velazquez, Francisco,Gavalas, Stephen,Wu, Wanli,Chen, Kevin X.,Nair, Anilkumar G.,Bennett, Frank,Huang, Yuhua,Pinto, Patrick,Jiang, Yueheng,Selyutin, Oleg,Vibulbhan, Bancha,Zeng, Qingbei,Lesburg, Charles,Duca, Jose,Heimark, Larry,Huang, Hsueh-Cheng,Agrawal, Sony,Jiang, Chuan-Kui,Ferrari, Eric,Li, Cheng,Kozlowski, Joseph,Rosenblum, Stuart,Shih, Neng-Yang,George Njoroge
, p. 447 - 458 (2014/01/17)
HCV infections are the leading causes for hepatocellular carcinoma and liver transplantation in the United States. Recent advances in drug discovery have identified direct acting antivirals which have significantly improved cure rates in patients. Current
TRICYCLIC INDOLE DERIVATIVES AND METHODS OF USE THEREOF
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Page/Page column 69; 70, (2010/01/07)
The present invention relates to Tricyclic Indole Derivatives, compositions comprising at least one Tricyclic Indole Derivatives, and methods of using the Tricyclic Indole Derivatives for treating or preventing a viral infection or a virus-related disorder in a patient