333994-00-6

TAK-220 is an orally bioavailable antagonist of chemokine (C-C motif) receptor 5 (CCR5). It binds to CCR5 (IC₅₀ = 3.5 nM for the human receptor in CHO cells), but not CCR1, CCR2b, CCR3, CCR4, or CCR7. TAK-220 inhibits the binding of chemokine (C-C motif) ligand 5 (CCL5) and CCL3 to CCR5 (IC₅₀s = 3.5 and 1.4 nM, respectively) but does not inhibit binding of CCL4. It inhibits HIV-1 envelope-mediated membrane fusion in a macrophage (M-tropic) R5, but not in a T cell (T-tropic) X4, strain of HIV-1 (IC₅₀s = 0.42 and >1,000 nM, respectively). TAK-220 inhibits the replication of six strains of R5 HIV-1 clinical isolates (EC₉₀ overall mean = 13 nM) and the R5 JR-FL laboratory-adapted strain (EC₅₀ = 0.6 nM), but not of X4 HIV-1 clinical isolates or the X4 IIIB laboratory-adapted strain (EC₅₀s = >10,000 nM for both), in human peripheral blood mononuclear cells (PBMCs).

TAK-220 is a selective and orally bioavailable CCR5 antagonist, with IC50s of 3.5 nM and 1.4 nM for inhibition on the binding of RANTES and MIP-1α to CCR5, respectively, but shows no effect on the binding to CCR1, CCR2b, CCR3, CCR4, or CCR7; TAK-220 also selectively inhibits HIV-1, with EC50s of 1.2 nM (HIV-1 KK), 0.72 nM (HIV-1 CTV), 1.7 nM (HIV-1 HKW), 1.7 nM (HIV-1 HNK), 0.93 nM (HIV-1 HTN), and 0.55 nM (HIV-1 HHA), and EC90s of 12 nM (HIV-1 KK), 5 nM (HIV-1 CTV), 12 nM (HIV-1 HKW), 28 nM (HIV-1 HNK), 15 nM (HIV-1 HTN), and 4 nM (HIV-1 HHA) in PBMCs.

MIP-1α-CCR5: 1.4 nM (IC₅₀, in CHO cells); RANTES-CCR5: 3.5 nM (IC₅₀, in CHO cells); HIV-1 (HHA): 0.55 nM (EC₅₀, in PBMCs); HIV-1 (CTV): 0.72 nM (EC₅₀, in PBMCs); HIV-1 (HTN): 0.93 nM (EC₅₀, in PBMCs); HIV-1 (KK): 1.2 nM (EC₅₀, in PBMCs); HIV-1 (HKW): 1.7 nM (EC₅₀, in PBMCs); HIV-1 (HNK): 1.7 nM (EC₅₀, in PBMCs); HIV-1 (HHA): 4 nM (EC90, in PBMCs); HIV-1 (CTV): 5 nM (EC90, in PBMCs); HIV-1 (KK): 12 nM (EC90, in PBMCs); HIV-1 (HKW): 12 nM (EC90, in PBMCs); HIV-1 (HTN): 15 nM (EC90, in PBMCs); HIV-1 (HNK): 28 nM (EC90, in PBMCs)

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[1] Takashima K, et al. Highly potent inhibition of human immunodeficiency virus type 1 replication by TAK-220, an orally bioavailable small-molecule CCR5 antagonist. Antimicrob Agents Chemother. 2005 Aug;49(8):3474-82. DOI:10.1128/AAC.49.8.3474-3482.2005
[2] Tremblay CL, et al. TAK-220, a novel small-molecule CCR5 antagonist, has favorable anti-human immunodeficiency virus interactions with other antiretrovirals in vitro. Antimicrob Agents Chemother. 2005 Aug;49(8):3483-5. DOI:10.1128/AAC.49.8.3483-3485.2005