TAK-220

TAK-220化学性质

TAK-220性质、用途与生产工艺

生物活性 TAK-220 是一种选择性的，可口服的 CCR5 拮抗剂，能够抑制 RANTES，MIP-1α 与 CCR5 结合，IC50 值分别为 3.5 nM 和 1.4 nM，但是对 CCR1，CCR2b，CCR3，CCR4 或者 CCR7 无作用; TAK-220 也可选择性地抑制 HIV-1，在外周单核细胞中，EC50 值分别为 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) 和 0.55 nM (HIV-1 HHA)，EC90 值分别为 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) 及 4 nM (HIV-1 HHA)。

靶点

RANTES-CCR5

3.5 nM (IC ₅₀ , in CHO cells)

MIP-1α-CCR5

1.4 nM (IC ₅₀ , in CHO cells)

HIV-1 (KK)

1.2 nM (EC ₅₀ , in PBMCs)

HIV-1 (CTV)

0.72 nM (EC ₅₀ , in PBMCs)

HIV-1 (HKW)

1.7 nM (EC ₅₀ , in PBMCs)

HIV-1 (HNK)

1.7 nM (EC ₅₀ , in PBMCs)

HIV-1 (HTN)

0.93 nM (EC ₅₀ , in PBMCs)

HIV-1 (HHA)

0.55 nM (EC ₅₀ , in PBMCs)

HIV-1 (KK)

12 nM (EC90, in PBMCs)

HIV-1 (CTV)

5 nM (EC90, in PBMCs)

HIV-1 (HKW)

12 nM (EC90, in PBMCs)

HIV-1 (HNK)

28 nM (EC90, in PBMCs)

HIV-1 (HTN)

15 nM (EC90, in PBMCs)

HIV-1 (HHA)

4 nM (EC90, in PBMCs)

体外研究

TAK-220 is a selective CCR5 antagonist, with IC ₅₀ s of 3.5 nM and 1.4 nM for inhibition on the binding of RANTES and MIP-1α to CCR5 in CHO cells, respectively, but shows no effect on the binding to CCR1, CCR2b, CCR3, CCR4, or CCR7. TAK-220 (0-1000 nM) interacts with CCR5 but not with RANTES and inhibits the CCR5-mediated Casup>2+ signaling. TAK-220 inhibits R5 HIV-1 (JR-FL) envelope-mediated membrane fusion, with an IC ₅₀ value of 0.42 nM, but does not alter X4 HIV-1 (HXB2) envelope-mediated membrane fusion. TAK-220 also selectively inhibits HIV-1, with EC ₅₀ s 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 EC ₉₀ s 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. TAK-220 shows potent inhibitory activity against the R5 isolates, with IC ₅₀ s of 3.12 nM against HIV-1 R5-08, 13.47 nM against HIV-1 R5-06, and 2.26 nM against HIV-1 R5-18. TAK-220 (>100 nM) has no toxicity in uninfected PBMCs.