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

• 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
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.03.118

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.