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.
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.
Bridger
Gary J
GJ
AnorMED Inc. now Genzyme Corporation, 500 Kendall Street, Cambridge, Massachusetts 02142, USA. gary.bridger@genzyme.com
Skerlj
Renato T
RT
Hernandez-Abad
Pedro E
PE
Bogucki
David E
DE
Wang
Zhongren
Z
Zhou
Yuanxi
Y
Nan
Susan
S
Boehringer
Eva M
EM
Wilson
Trevor
T
Crawford
Jason
J
Metz
Markus
M
Hatse
Sigrid
S
Princen
Katrien
K
De Clercq
Erik
E
Schols
Dominique
D
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008956:Models, Chemical; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes; D014779:Virus Replication / Q000187:drug effects*
D019380:Anti-HIV Agents; D006571:Heterocyclic Compounds; C503590:N-(1,4,8,11- tetraazacyclotetradecanyl-1,4-phenylenebis(methylene))-2-(aminomethyl)- pyridine; D011725:Pyridines; D019718:Receptors, CXCR4