Synthesis and SAR of novel CXCR4 antagonists that are potent inhibitors of T tropic (X4) HIV-1 replication.
An early lead from the AMD070 program was optimized and a structure-activity relationship was developed for a novel series of heterocyclic containing compounds. Potent CXCR4 antagonists were identified based on anti-HIV-1 activity and Ca(2+) flux inhibition that displayed good pharmacokinetics in rat and dog.
Genzyme Corp, 153 Second Avenue, Waltham, MA 02451, USA. renato.skerlj@genzyme.com
Renato
R
Skerlj
Gary
G
Bridger
Ernie
E
McEachern
Curtis
C
Harwig
Chris
C
Smith
Trevor
T
Wilson
Duane
D
Veale
Helen
H
Yee
Jason
J
Crawford
Krystyna
K
Skupinska
Rossana
R
Wauthy
Wen
W
Yang
Yongbao
Y
Zhu
David
D
Bogucki
Maria
M
Di Fluri
Jonathon
J
Langille
Dana
D
Huskens
Erik
E
De Clercq
Dominique
D
Schols
D000284:Administration, Oral; D000634:Aminoquinolines; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001562:Benzimidazoles; D002082:Butylamines; D020013:Calcium Signaling; D004285:Dogs; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D006801:Humans; D051381:Rats; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects*
D000634:Aminoquinolines; D019380:Anti-HIV Agents; D001562:Benzimidazoles; D002082:Butylamines; D006573:Heterocyclic Compounds, 1-Ring; D019718:Receptors, CXCR4; C494414:mavorixafor