Identification of a novel series of potent HCV NS5B Site I inhibitors

Efforts investigating spatially comparative alternates of the ethylene-bridged piperazine in BMS-791325 that would offer a maintained or improved virologic and pharmacokinetic profile have been multifaceted. One foray involved the utilization of various octahydropyrrolo[3,4-c]pyrrole propellanes. Ma...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2014-04, Vol.24 (8), p.1993-1997
Main Authors: Eastman, Kyle J, Yang, Zhong, Bender, John A, Mosure, Kathy, Lemm, Julie A, Meanwell, Nicholas A, Roberts, Susan B, Knipe, Jay, Kadow, John F
Format: Article
Language:English
Subjects:
Animals
Antiviral Agents - chemistry
Antiviral Agents - pharmacokinetics
Benzazepines - chemistry
Hepacivirus
Hepatitis C virus
Indoles - chemistry
Molecular Structure
Rats
Viral Nonstructural Proteins - antagonists & inhibitors
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Summary:Efforts investigating spatially comparative alternates of the ethylene-bridged piperazine in BMS-791325 that would offer a maintained or improved virologic and pharmacokinetic profile have been multifaceted. One foray involved the utilization of various octahydropyrrolo[3,4-c]pyrrole propellanes. Many of the propellane analogs described in this work exhibited better than targeted potency (less than 20 nM). Additionally, improved exposure in rats was achieved through the employment of two newly invented and now readily accessible carbon bridged propellanes as compared to their heteroatom bridged analogs.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2014.02.047