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Background:  In 1999, we reported the first small-molecule CCR5 antagonist TAK-779 as a highly potent and selective inhibitor of HIV-1 replication. However, this compound could not be further developed because of its poor oral bioavailability. In 2003, we presented TAK-220, an orally bioavailable CCR5 antagonist with potent anti-HIV-1 activity. TAK-220 is a novel series of compounds, of which chemical structure totally differs from that of TAK-779. Our continuous efforts have recently identified TAK-652, an orally bioavailable TAK-779 derivative with more potent anti-HIV-1 activity.

Methods:  Inhibition of chemokine binding by TAK-652 was evaluated using various chemokine receptor-expressing cells and their ligands. The anti-HIV-1 activity was determined in several CCR5-expressing cell lines and peripheral blood mononuclear cells (PBMC). A double-blind, placebo-controlled, single oral dose study was conducted to evaluate the safety, tolerability, and pharmacokinetics of TAK-652 in healthy male volunteers.

Results:  TAK-652 inhibited the binding of RANTES, MIP-1α, and MIP-1β to CCR5-expressing cells with an IC₅₀ of 3.1, 2.3, and 2.3 nM, respectively. TAK-652 could also suppress the binding of MCP-1 to CCR2b-expressing cells with an IC₅₀ of 5.9 nM. TAK-652 was slightly inhibited the ligand-binding to CCR3- and CCR4-expressing cells and did not affect the ligand-binding to CCR1- and CCR7-expressing cells even at a concentration of 10 μM. TAK-652 selectively inhibited R5 HIV-1 but not X4 HIV-1 replication. Furthermore, TAK-652 inhibited the replication of 6 R5 HIV-1 clinical isolates, including reverse transcriptase- and protease inhibitor-resistant mutants, in PBMC with a mean EC₅₀ of 0.061 nM and a mean EC₉₀ of 0.25 nM. In addition, all recombinant HIV-1 strains with 7 different subtype (A to G) envelope proteins were equally susceptible to TAK-652 with a mean IC₅₀ of 1.0 nM. The anti-HIV-1 activity of TAK-652 decreased 5-fold in the presence of high concentrations of human serum. Single oral administration (25 to 100 mg) of TAK-652 solution was safe and well tolerated. TAK-652 showed good oral absorption, and its plasma concentration at 24 hours after administration (25 mg) was 7 ng/mL (8.8 nM).

Conclusions:  TAK-652 is an orally bioavailable CCR5 antagonist with a highly potent anti-HIV-1 activity in vitro and excellent pharmacological profiles in vivo (possible once daily administration), indicating a promising candidate as a novel entry inhibitor of HIV-1.

Keywords: TAK-652; Entry inhibitor; CCR5 antagonist