10th Conference on Retroviruses and Opportunistic Infections Boston, MA USA - February 10 -14, 2003

Conf Retroviruses Opportunistic Infect 2003 Feb 10-14;10th: abstract no. 11
Y. Iizawa¹, N. Kanzaki¹, K. Takashima¹, H. Miyake^1,2, Y. Tagawa¹, Y. Sugihara¹, M. Baba^2
1Takeda Chemical Industries, Ltd, Osaka, Japan and ²Kagoshima Univ, Japan

BACKGROUND: There is an urgent need for the development of anti-HIV-1 drugs with a new mode of action because of the emergence of multi-drug resistance to existing classes of compounds, such as reverse transcriptase (RT) and protease inhibitors. In 1999, we have reported TAK-779 as a novel CCR5 antagonist with highly potent inhibitor of R5 HIV-1 replication in cell cultures. However, TAK-779 was a parenteral drug and its development was discontinued by the irritation at the injection site. Our continuous efforts to find effective CCR5 antagonists have recently allowed us to identify TAK-220, an orally bioavailable CCR5 antagonist.

METHODS: Receptor binding properties of TAK-220 were determined by ligand binding assay using various chemokine receptor-expressing cells and their ligands. Anti-HIV-1 activity of TAK-220 was determined using several CCR5-expressing cell lines and PBMCs. Pharmacokinetic properties of TAK-220 were determined in rats and monkeys.

RESULTS: TAK-220 inhibited the binding of RANTES and MIP-1alpha to CCR5-expressing cells with IC₅₀s of 3.5 and 1.4 nmol/L, respectively, but did not inhibit the binding of MIP-1beta even at a concentration of 10 mumol/L. TAK-220 did not inhibit the ligand-binding to CCR1-, CCR2b-, CCR3-, CCR4-, or CCR7-expressing cells even at a concentration of 10 mumol/L, suggesting high specificity of TAK-220 to CCR5. TAK-220 selectively inhibited HIV-1 infection mediated by CCR5. TAK-220 inhibited the replication of six R5 HIV-1 clinical isolates, including resistant mutants to RT and protease inhibitors, in PBMCs with mean EC₅₀ and EC₉₀ of 1.1 and 13 nmol/L, respectively. Anti-HIV-1 activity of TAK-220 was unaffected by addition of high concentrations of human serum. When TAK-220 was administered orally to fasted rats and monkeys at a dose of 5 mg/kg, its bioavailability was 9.5 and 28.9 %, respectively. Furthermore, the concentration of TAK-220 in lymph fluid of rats was about twice as high as that in plasma.

CONCLUSIONS: TAK-220 is an orally bioavailable CCR5 antagonist with a potent anti-R5 HIV-1 activity, indicating a promising candidate as an anti-HIV-1 drug.

030210
11

Copyright © 2003 - Foundation for Retrovirology and Human Health. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health. Licensed (AIDSLINE) from National Library of Medicine.