TAK-779

TAK-779 is an antagonist of chemokine receptor 5 (CCR5), CCR2b, and CXC chemokine receptor 3 (CXCR3).^1,2 It inhibits CCR5 and CXCR3 (IC₅₀s = 236 and 369 nM, respectively, for mouse recombinant receptors expressed in 2B4 T cells) and CCR5 and CCR2b (IC₅₀s = 1.4 and 27 nM, respectively, for human recombinant receptors expressed in CHO cells). TAK-779 inhibits the replication of clinical isolates of R5, but not X4, HIV-1 in human peripheral blood mononuclear cells (PBMCs; EC₅₀s = 1.6-3.5 and >20,000 nM, respectively).¹ TAK-779 (250 mg/animal per day) inhibits ovalbumin-induced increases in CCR5, CXCR3, IFN-γ, and TNF-α expression in mouse lung, as well as the number of total cells, lymphocytes, and eosinophils in bronchoalveolar lavage fluid (BALF), in a mouse model of asthma.³ It also increases intestinal allograft survival in a rat model of small intestine transplantation when administered at a dose of 10 mg/kg per day.⁴

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1. Baba, M., Nishimura, O., Kanzaki, N., et al. A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proc. Natl. Acad. Sci. USA 96(10), 5698-5703 (1999).

2. Gao, P., Zhou, X.-Y., Yashiro-Ohtani, Y., et al. The unique target specificity of a nonpeptide chemokine receptor antagonist: Selective blockade of two Th1 chemokine receptors CCR5 and CXCR3. J. Leukoc. Biol. 73(2), 273-280 (2003).

3. Suzaki, Y., Hamada, K., Nomi, T., et al. A small-molecule compound targeting CCR5 and CXCR3 prevents airway hyperresponsiveness and inflammation. Eur. J. Respir. J. 31(4), 783-789 (2008).

4. Takama, Y., Miyagawa, S., Yamamoto, A., et al. Effects of a calcineurin inhibitor, FK506, and a CCR5/CXCR3 antagonist, TAK-779, in a rat small intestinal transplantation model. Transpl. Immunol. 25(1), 49-55 (2011).