title: 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.affiliation: Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima 890-8544, Japan. baba@m.kufm.kagoshima-u.ac.jp
authors.forename: Masanori
authors.initials: M
authors.lastname: Baba
authors.forename: Katsunori
authors.initials: K
authors.lastname: Takashima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyake
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kanzaki
authors.forename: Koichiro
authors.initials: K
authors.lastname: Teshima
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Shiraishi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Iizawa
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000378:metabolism; D006224:Cricetinae; D004311:Double-Blind Method; D015497:HIV-1 / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000821:virology; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008561:Membrane Fusion / Q000187:drug effects; D019713:Receptors, CCR5 / Q000502:physiology; D013454:Sulfoxides
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D007093:Imidazoles; D019402:Macrophage Inflammatory Proteins; D019713:Receptors, CCR5; D013454:Sulfoxides; C506967:cenicriviroc