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 isoquinoline series led to a number of compounds with low nanomolar anti-HIV activities and promising rat PK properties.
Miller
John F
JF
Department of Medicinal Chemistry, Infectious Diseases Center for Excellence in Drug Discovery, GlaxoSmithKline Research and Development, Research Triangle Park, NC 27709-3398, USA. john.6.miller@gsk.com
Gudmundsson
Kristjan S
KS
D'Aurora Richardson
Leah
L
Jenkinson
Stephen
S
Spaltenstein
Andrew
A
Thomson
Michael
M
Wheelan
Pat
P
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001562:Benzimidazoles / Q000737:chemistry; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D001562:Benzimidazoles; D007546:Isoquinolines; D019718:Receptors, CXCR4; C031000:benzimidazole