Discovery of SCH 900188: A Potent Hepatitis C Virus NS5B Polymerase Inhibitor Prodrug As a Development Candidate

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,...

Full description

Saved in:

Bibliographic Details
Published in:	ACS medicinal chemistry letters Vol. 5; no. 3; pp. 244 - 248
Main Authors:	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
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 13-03-2014
Subjects:	Letter prodrug hepatitis C virus polymerase inhibitor HCV NS5B polymerase
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1948-5875 1948-5875
DOI:	10.1021/ml400192w