TAK-779

Category	Human immunodeficiency Virus (HIV)
CAS	229005-80-5
Description	TAK-779 is a potent, dual antagonist at chemokine receptors CCR2 and CCR5 with IC50 = 1.4 nM at CCR5 and 2.3 nM at CCR2. Antagonists of both CCR2 and CCR5 such as TAK-779 have been investigated for treatment of viruses, rheumatoid arthritis, multiple sclerosis, and cancer. CCR5 is particularly targeted for anti-HIV therapy, since HIV entry into cells requires chemokine coreceptors CCR5 and CXCR4.

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Product Information

Synonyms	N,N-Dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzohepten-8-yl]carbonyl]amino]benzyl]tetrahydro-2H-pyran-4-aminium chloride, TAK-799; TAK 779; TAK779; Takeda 779
Molecular Weight	531.13
Molecular Formula	C33H39ClN2O2
Canonical SMILES	CC1=CC=C(C=C1)C2=CC3=C(CCCC(=C3)C(=O)NC4=CC=C(C=C4)C[N+](C)(C)C5CCOCC5)C=C2.[Cl-]
InChI	InChI=1S/C33H38N2O2.ClH/c1-24-7-11-27(12-8-24)28-14-13-26-5-4-6-29(22-30(26)21-28)33(36)34-31-15-9-25(10-16-31)23-35(2,3)32-17-19-37-20-18-32;/h7-16,21-22,32H,4-6,17-20,23H2,1-3H3;1H
InChIKey	VDALIBWXVQVFGZ-UHFFFAOYSA-N
Purity	>98%
Solubility	In Vitro: DMSO : ≥ 25 mg/mL (47.07 mM) H2O : 16.66 mg/mL (31.37 mM; Need ultrasonic and warming)
Appearance	White to off-white (Solid)
Storage	-20°C, sealed storage, away from moisture * In solvent : -80°C, 6 months -20°C, 1 month (sealed storage, away from moisture)
Animal Admin	The mice are immunized with MOG and are treated s.c. with TAK-779 or vehicle. The mice (N= 10) are injected s.c. with 150 µg TAK-779 (dissolved in 5% mannitol solution) in a volume of 100 µL, once daily after MOG immunization. TAK-779 injection is started from day 0 after immunization and continued once daily for 22 days. The dose of 150 µg is determined based on the observations in prior experiments that the dose of 50 µg per mouse can not produce inhibition, and a dose of more than 100 µg per mouse is required to produce significant inhibition. The dose of 150 µg per mouse has also been used in other mouse experimental models, and approximately the same dose is used in allograft rejection and asthma models. As a control, an equal volume of PBS containing 5% mannitol is injected daily in the control mice (N= 10).
Complexity	769
Exact Mass	530.2700062
In Vitro	TAK-779 is a potent and selective nonpeptide antagonist of CCR5, with a Ki of 1.1 nM, and effectively and selectively inhibits R5 HIV-1, with EC50 and EC90 of 1.2 nM and 5.7 nM, respectively, in MAGI-CCR5 cells. TAK-779 less potently blocks the binding of [125I]-monocyte chemotactic protein 1 to CCR2b in CHO/CCR2b cells, with an IC50 for CCR2b of 27 nM. TAK-779 also completely inhibits the binding of [125I]-RANTES to CHO/CCR5 cells with an IC50 of 1.4 nM. TAK-779 (20 nM) selectively inhibits CCR5-mediated Ca2+-signaling. In addition, TAK-779 shows no inhibition on X4 HIV-1 strains. TAK-779 is an antagonist of CXCR3, and inhibits the migration of T cells but not T cell proliferation.
In Vivo	TAK-779 (10 mg/kg per day, s.c.) significantly prolongs the allograft survival of the rat intestinal transplantation model. TAK-779 also decreases the number of CD4+ as well as CD8+ T cells in spleen, blood and recipient mesenteric lymph nodes (MLN). TAK-779 (150 µg per mouse, s.c.) supppresses the development of experimental autoimmune encephalomyelitis (EAE) in myelin oligodendrocyte glycoprotein (MOG)-immunized C57BL/6 mice. TAK-779 decreases the infiltration of CXCR3 and CCR5 bearing leukocytes into the spinal cord. TAK-779 does not alter myelin oligodendrocyte glycoprotein (MOG)-specific immune responses or affect the potential of MOG-specific T cells to transfer experimental autoimmune encephalomyelitis (EAE).
PSA	26.30000
Target	CCR; HIV; CXCR