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Title: Synthesis and structure-activity relationships of azamacrocyclic C-X-C chemokine receptor 4 antagonists: analogues containing a single azamacrocyclic ring are potent inhibitors of T-cell tropic (X4) HIV-1 replication
Authors: Bridger, Gary J ×
Skerlj, Renato T
Hernandez-Abad, Pedro E
Bogucki, David E
Wang, Zhongren
Zhou, Yuanxi
Nan, Susan
Boehringer, Eva M
Wilson, Trevor
Crawford, Jason
Metz, Markus
Hatse, Sigrid
Princen, Katrien
De Clercq, Erik
Schols, Dominique #
Issue Date: Feb-2010
Publisher: ACS Publications
Series Title: Journal of Medicinal Chemistry vol:53 issue:3 pages:1250-1260
Abstract: Bis-tetraazamacrocycles such as the bicyclam AMD3100 (1) are a class of potent and selective anti-HIV-1 agents that inhibit virus replication by binding to the chemokine receptor CXCR4, the coreceptor for entry of X4 viruses. By sequential replacement and/or deletion of the amino groups within the azamacrocyclic ring systems, we have determined the minimum structural features required for potent antiviral activity in this class of compounds. All eight amino groups are not required for activity, the critical amino groups on a per ring basis are nonidentical, and the overall charge at physiological pH can be reduced without compromising potency. This approach led to the identification of several single ring azamacrocyclic analogues such as AMD3465 (3d), 36, and 40, which exhibit EC(50)'s against the cytopathic effects of HIV-1 of 9.0, 1.0, and 4.0 nM, respectively, antiviral potencies that are comparable to 1 (EC(50) against HIV-1 of 4.0 nM). More importantly, however, the key structural elements of 1 required for antiviral activity may facilitate the design of nonmacrocyclic CXCR4 antagonists suitable for HIV treatment via oral administration.
URI: 
ISSN: 0022-2623
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)
Laboratory of Experimental Oncology
× corresponding author
# (joint) last author

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