132997-77-4Relevant articles and documents
Discovery and early clinical evaluation of BMS-605339, a potent and orally efficacious tripeptidic acylsulfonamide ns3 protease inhibitor for the treatment of hepatitis C virus infection
Scola, Paul M.,Wang, Alan Xiangdong,Good, Andrew C.,Sun, Li-Qiang,Combrink, Keith D.,Campbell, Jeffrey A.,Chen, Jie,Tu, Yong,Sin, Ny,Venables, Brian L.,Sit, Sing-Yuen,Chen, Yan,Cocuzza, Anthony,Bilder, Donna M.,D'Andrea, Stanley,Zheng, Barbara,Hewawasam, Piyasena,Ding, Min,Thuring, Jan,Li, Jianqing,Hernandez, Dennis,Yu, Fei,Falk, Paul,Zhai, Guangzhi,Sheaffer, Amy K.,Chen, Chaoqun,Lee, Min S.,Barry, Diana,Knipe, Jay O.,Li, Wenying,Han, Yong-Hae,Jenkins, Susan,Gesenberg, Christoph,Gao, Qi,Sinz, Michael W.,Santone, Kenneth S.,Zvyaga, Tatyana,Rajamani, Ramkumar,Klei, Herbert E.,Colonno, Richard J.,Grasela, Dennis M.,Hughes, Eric,Chien, Caly,Adams, Stephen,Levesque, Paul C.,Li, Danshi,Zhu, Jialong,Meanwell, Nicholas A.,McPhee, Fiona
, p. 1708 - 1729 (2014/04/03)
The discovery of BMS-605339 (35), a tripeptidic inhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropylacylsulfonamide moiety that was designed to improve the potency of carboxylic acid prototypes through the introduction of favorable nonbonding interactions within the S1′ site of the protease. The identification of 35 was enabled through the optimization and balance of critical properties including potency and pharmacokinetics (PK). This was achieved through modulation of the P2* subsite of the inhibitor which identified the isoquinoline ring system as a key template for improving PK properties with further optimization achieved through functionalization. A methoxy moiety at the C6 position of this isoquinoline ring system proved to be optimal with respect to potency and PK, thus providing the clinical compound 35 which demonstrated antiviral activity in HCV-infected patients.
Compounds for PIM kinase inhibition and for treating malignancy
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, (2011/06/26)
The present invention relates to the compounds of formula I as well as to their use as PIM kinase inhibitors and, thereby, their use for treating oncological diseases, particularly of the hematopoietic system, the liver and the prostate gland
Fragment-based discovery of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors
Ray, Peter,Wright, Jane,Adam, Julia,Bennett, Johnathan,Boucharens, Sylviane,Black, Darcey,Cook, Andrew,Brown, Angus R.,Epemolu, Ola,Fletcher, Dan,Haunso, Anders,Huggett, Margaret,Jones, Phil,Laats, Steven,Lyons, Amanda,Mestres, Jordi,De Man, Jos,Morphy, Richard,Rankovic, Zoran,Sherborne, Brad,Sherry, Lorcan,Van Straten, Nicole,Westwood, Paul,Zaman, Guido Z.R.
supporting information; scheme or table, p. 97 - 101 (2011/02/28)
Fragment-based NMR screening of a small literature focused library led to identification of a historical thrombin/FactorXa building block, 17A, that was found to be a ROCK-I inhibitor. In the absence of an X-ray structure, fragment growth afforded 6-substituted isoquinolin-1-amine derivatives which were profiled in the primary ROCK-I IMAP assay. Compounds 23A and 23E were selected as fragment optimized hits for further profiling. Compound 23A has similar ROCK-1 affinity, potency and cell based efficacy to the first generation ROCK inhibitors, however, it has a superior PK profile in C57 mouse. Compound 23E demonstrates the feasibility of improving ROCK-1 affinity, potency and cell based efficacy for the series, however, it has a poor PK profile relative to 23A.
