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

John F Miller; Kristjan S Gudmundsson; Leah D'Aurora Richardson; Stephen Jenkinson; Andrew Spaltenstein; Michael Thomson; Pat Wheelan

doi:10.1016/j.bmcl.2010.03.118

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

Bioorg Med Chem Lett. 2010 May 15;20(10):3026-30. doi: 10.1016/j.bmcl.2010.03.118.

Authors

John F Miller¹, Kristjan S Gudmundsson, Leah D'Aurora Richardson, Stephen Jenkinson, Andrew Spaltenstein, Michael Thomson, Pat Wheelan

Affiliation

¹ Department of Medicinal Chemistry, Infectious Diseases Center for Excellence in Drug Discovery, GlaxoSmithKline Research and Development, Research Triangle Park, NC 27709-3398, USA. [email protected]

PMID: 20443225
DOI: 10.1016/j.bmcl.2010.03.118

Abstract

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.

MeSH terms

Animals
Anti-HIV Agents / chemical synthesis*
Anti-HIV Agents / chemistry
Anti-HIV Agents / pharmacokinetics
Benzimidazoles / chemistry
Isoquinolines / chemical synthesis
Isoquinolines / chemistry*
Isoquinolines / pharmacokinetics
Rats
Receptors, CXCR4 / antagonists & inhibitors*
Receptors, CXCR4 / metabolism
Structure-Activity Relationship

Substances

Anti-HIV Agents
Benzimidazoles
Isoquinolines
Receptors, CXCR4
benzimidazole