TAK-779 is a highly potent and selective nonpeptide CCR5 antagonist with a IC50 value of 1.4 nM in the binding assay. TAK-779 also inhibits the replication of macrophage (M)-tropic HIV-1 (Ba-L strain) in both MAGI-CCR5 cells and PBMCs with EC50 values of 1.2 and 3.7 nM, respectively.
TAK-779 demonstrates potent and selective nonpeptide antagonism against CCR5, exhibiting a Ki of 1.1 nM. It effectively and selectively inhibits R5 HIV-1, with EC50 and EC90 values of 1.2 nM and 5.7 nM, correspondingly, in MAGI-CCR5 cells. Although less potent, TAK-779 partially impedes the binding of [125I]-monocyte chemotactic protein 1 to CCR2b in CHO/CCR2b cells, with an IC50 of 27 nM. Moreover, it entirely blocks the binding of [125I]-RANTES to CHO/CCR5 cells, with an IC50 of 1.4 nM. At a concentration of 20 nM, TAK-779 selectively hampers CCR5-mediated Ca2+-signaling. Notably, TAK-779 exhibits no inhibitory effect on X4 HIV-1 strains. TAK-779 functions as a CXCR3 antagonist, effectively impeding the migration of T cells while leaving T cell proliferation unaffected.
TAK-779 动物研究
Animal study
TAK-779 (10 mg/kg per day, sC.) significantly extends the survival of allografts in a rat intestinal transplantation model. Additionally, TAK-779 reduces the count of CD4+ and CD8+ T cells in the spleen, blood, and mesenteric lymph nodes (MLN) of recipients.TAK-779 administered subcutaneously at a dose of 150 µg per mouse suppresses the development of experimental autoimmune encephalomyelitis (EAE) in MOG-immunized C57BL/6 mice. It reduces the infiltration of leukocytes bearing CXCR3 and CCR5 into the spinal cord. TAK-779 does not modulate MOG-specific immune responses or the ability of MOG-specific T cells to induce experimental autoimmune encephalomyelitis (EAE).
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