Synthesis and SAR of novel isoquinoline CXCR4 antagonists with potent anti-HIV activity

Using AMD070 as a starting point for structural modification, a novel series of isoquinoline CXCR4 antagonists was developed. A structure–activity scan of alternate lower heterocycles led to the 3-isoquinolinyl moiety as an attractive replacement for benzimidazole. Side chain optimization in the iso...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2010-05, Vol.20 (10), p.3026-3030
Main Authors: Miller, John F., Gudmundsson, Kristjan S., Richardson, Leah D’Aurora, Jenkinson, Stephen, Spaltenstein, Andrew, Thomson, Michael, Wheelan, Pat
Format: Article
Language:English
Subjects:
AMD070
Animals
Anti-HIV Agents - chemical synthesis
Anti-HIV Agents - chemistry
Anti-HIV Agents - pharmacokinetics
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral
Antiviral agents
Benzimidazoles - chemistry
Biological and medical sciences
CXCR4
HIV
Human immunodeficiency virus
Isoquinoline
Isoquinolines - chemical synthesis
Isoquinolines - chemistry
Isoquinolines - pharmacokinetics
Medical sciences
Pharmacology. Drug treatments
Rats
Receptors, CXCR4 - antagonists & inhibitors
Receptors, CXCR4 - metabolism
Structure-Activity Relationship
Tetrahydroquinoline
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Summary:Using AMD070 as a starting point for structural modification, a novel series of isoquinoline CXCR4 antagonists was developed. A structure–activity scan of alternate lower heterocycles led to the 3-isoquinolinyl moiety as an attractive replacement for benzimidazole. Side chain optimization in the isoquinoline series led to a number of compounds with low nanomolar anti-HIV activities and promising rat PK properties. Using AMD070 as a starting point for structural modification, a novel series of isoquinoline CXCR4 antagonists was developed. A structure–activity scan of alternate lower heterocycles led to the 3-isoquinolinyl moiety as an attractive replacement for benzimidazole. Side chain optimization in the isoquinoline series led to a number of compounds with low nanomolar anti-HIV activities and promising rat PK properties.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2010.03.118