TAK-652 inhibits CCR5-mediated human immunodeficiency virus type 1 infection in vitro and has favorable pharmacokinetics in humans.

Abstract

The first small-molecule CCR5 antagonist, TAK-779, could not be developed as an anti-human immunodeficiency virus type (anti-HIV-1) agent because of its poor oral bioavailability. TAK-652 is an orally bioavailable TAK-779 derivative with potent anti-HIV-1 activity. TAK-652 inhibited the binding of RANTES (regulated on activation, normal T-cell expressed and secreted), macrophage inflammatory protein 1alpha (MIP-1alpha), and MIP-1beta to CCR5-expressing cells at nanomolar concentrations. TAK-652 could also suppress the binding of monocyte chemotactic protein 1 (MCP-1) to CCR2b-expressing cells. However, its inhibitory effect on ligand binding to other chemokine receptors was limited. TAK-652 was active against CCR5-using (R5) HIV-1 but totally inactive against CXCR4-using (X4) HIV-1. The compound was active against R5 HIV-1 clinical isolates containing reverse transcriptase and protease inhibitor-resistant mutations, with a mean 50% effective concentration (EC50) and EC90 of 0.061 and 0.25 nM, respectively. In addition, recombinant R5 viruses carrying different subtype (A to G) envelope proteins were equally susceptible to TAK-652. A single oral administration of TAK-652 up to 100 mg was safe and well tolerated in humans. The compound displayed favorable pharmacokinetics, and its plasma concentration was 7.2 ng/ml (9.1 nM) even 24 h after the administration of 25 mg. Thus, TAK-652 is a promising candidate as a novel entry inhibitor of HIV-1.

• Authors: Masanori Baba, Katsunori Takashima, Hiroshi Miyake, Naoyuki Kanzaki, Koichiro Teshima, Xin Wang, Mitsuru Shiraishi, Yuji Iizawa
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 49 Issue 11 Pg. 4584-91 (Nov 2005) ISSN: 0066-4804 [Print] United States
• PMID: 16251299 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-HIV Agents
• CCR5 Receptor Antagonists
• Chemokine CCL3
• Chemokine CCL4
• Chemokine CCL5
• Imidazoles
• Macrophage Inflammatory Proteins
• Receptors, CCR5
• Sulfoxides
• cenicriviroc

Topics

• Animals
• Anti-HIV Agents (adverse effects, pharmacokinetics, pharmacology)
• CCR5 Receptor Antagonists
• CHO Cells
• Chemokine CCL3
• Chemokine CCL4
• Chemokine CCL5 (metabolism)
• Cricetinae
• Double-Blind Method
• HIV-1 (drug effects)
• HeLa Cells
• Humans
• Imidazoles (adverse effects, pharmacokinetics, pharmacology)
• Leukocytes, Mononuclear (virology)
• Macrophage Inflammatory Proteins (metabolism)
• Membrane Fusion (drug effects)
• Receptors, CCR5 (physiology)
• Sulfoxides