Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro.
We identified a novel spirodiketopiperazine (SDP) derivative, AK602/ONO4128/GW873140, which specifically blocked the binding of macrophage inflammatory protein 1alpha (MIP-1alpha) to CCR5 with a high affinity (K(d) of approximately 3 nM), potently blocked human immunodeficiency virus type 1 (HIV-1) gp120/CCR5 binding and exerted potent activity against a wide spectrum of laboratory and primary R5 HIV-1 isolates, including multidrug-resistant HIV-1 (HIV-1(MDR)) (50% inhibitory concentration values of 0.1 to 0.6 nM) in vitro. AK602 competitively blocked the binding to CCR5 expressed on Chinese hamster ovary cells of two monoclonal antibodies, 45523, directed against multidomain epitopes of CCR5, and 45531, specific against the C-terminal half of the second extracellular loop (ECL2B) of CCR5. AK602, despite its much greater anti-HIV-1 activity than other previously published CCR5 inhibitors, including TAK-779 and SCH-C, preserved RANTES (regulated on activation normal T-cell expressed and secreted) and MIP-1beta binding to CCR5(+) cells and their functions, including CC-chemokine-induced chemotaxis and CCR5 internalization, while TAK-779 and SCH-C fully blocked the CC-chemokine/CCR5 interactions. Pharmacokinetic studies revealed favorable oral bioavailability in rodents. These data warrant further development of AK602 as a potential therapeutic for HIV-1 infection.
Maeda
Kenji
K
Department of Hematology, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
Nakata
Hirotomo
H
Koh
Yasuhiro
Y
Miyakawa
Toshikazu
T
Ogata
Hiromi
H
Takaoka
Yoshikazu
Y
Shibayama
Shiro
S
Sagawa
Kenji
K
Fukushima
Daikichi
D
Moravek
Joseph
J
Koyanagi
Yoshio
Y
Mitsuya
Hiroaki
H
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D018946:Chemokine CCL5 / Q000378:metabolism; D019742:Chemokines, CC / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D006224:Cricetinae; D024882:Drug Resistance, Viral; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear; D008826:Microbial Sensitivity Tests; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
C489036:4-((4-((3R)-1-butyl-3-((1R)) cyclohexylhy-droxymethyl)-2,5-dioxo-1,4,9-triazaspiro(5.5)undec-9-yl methyl)phenoxy)benzoic acid hydrochloride; D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D018946:Chemokine CCL5; D019742:Chemokines, CC; D015699:HIV Envelope Protein gp120; D010879:Piperazines; D019713:Receptors, CCR5; D013141:Spiro Compounds