TAK-652 Inhibits CCR5-Mediated Human Immunodeficiency Virus Type 1 Infection In Vitro and Has Favorable Pharmacokinetics in Humans

• DOI: 10.1128/aac.49.11.4584-4591.2005
• Publication Date: 2005-10-26T16:37:59Z
• Authors: Masanori Baba; Katsunori Takashima; Hiroshi Miyake; Naoyuki Kanzaki; Koichiro Teshima; Xin Wang; Mitsuru Shiraishi; Yuji Iizawa
• Keywords: Chemokine receptor CCR5; Monocyte

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 orally bioavailable TAK-779 derivative with potent anti-HIV-1 activity. inhibited the binding RANTES (regulated on activation, normal T-cell expressed and secreted), macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta to CCR5-expressing cells at nanomolar concentrations. also suppress monocyte chemotactic 1 (MCP-1) CCR2b-expressing cells. However, inhibitory effect ligand other chemokine receptors was limited. active against CCR5-using (R5) HIV-1 but totally inactive CXCR4-using (X4) HIV-1. compound R5 clinical isolates containing reverse transcriptase protease inhibitor-resistant mutations, a mean 50% effective concentration (EC50) EC90 0.061 0.25 nM, respectively. In addition, recombinant viruses carrying different subtype (A G) envelope proteins were equally susceptible TAK-652. A single administration up 100 mg safe well tolerated in humans. displayed favorable pharmacokinetics, plasma 7.2 ng/ml (9.1 nM) even 24 h after 25 mg. Thus, promising candidate novel entry inhibitor