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    Zotarolimus (ABT578; A-179578)
    Zotarolimus (ABT578; A-179578)

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0208
    CAS #: 221877-54-9Purity ≥98%

    Description: Zotarolimus (also known as ABT-578; A 179578), a tetrazole-based and semi-synthetic analog of rapamycin, is a highly potent immunosuppressant with the potential to be used for preventing coronary artery restenosis. It inhibits FKBP-12 binding with an IC50 of 2.8 nM. It may have usefulness in the treatment of restenosis, immune, and autoimmune diseases. In human coronary artery cells, zotarolimus inhibited smooth muscle cell (SMC) and endothelial cell (EC) proliferation with IC50 values of 2.9 and 2.6 nM, respectively. In human blood-derived peripheral blood mononuclear cells (PBMC) and rat splenocytes, zotarolimus inhibited Con A-induced human and rat T cell proliferation with IC50 values of 7.0 and 1337 nM respectively in a concentration-dependent way. In lymphocytes derived from humans or rats, zotarolimus inhibited the human and rat mixed lymphocyte reaction (MLR) with IC50 values of 1.2 and 1465 nM respectively in a concentration-dependent way.

    References:Eur Heart J. 2006 Apr;27(8):988-93; J Cardiovasc Pharmacol. 2007 Apr;49(4):228-35.   

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    Molecular Weight (MW)

    966.21

    Formula

    C52H79N5O12

    CAS No.

    221877-54-9

    Storage

    -20℃ for 3 years in powder form

    -80℃ for 2 years in solvent

    Solubility (In vitro)

    DMSO: 100 mg/mL (103.5 mM)

    Water: <1 mg/mL

    Ethanol: 100 mg/mL (103.5 mM)

    Other info

    Chemical Name: (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,27-dihydroxy-10,21-dimethoxy-3-{(1R)-2-[(1S,3R,4S)-3-methoxy-4-(1H-tetrazol-1-yl)cyclohexyl]-1-methylethyl}-6,8,12,14,20,26-hexamethyl-4,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-heptadecahydro-3H-23,27-epoxypyrido[2,1-c][1,4]oxazacyclohentriacontine-1,5,11,28,29(6H,31H)-pentone
    InChi Key: CGTADGCBEXYWNE-JUKNQOCSSA-N
    InChi Code: InChI=1S/C52H79N5O12/c1-31-16-12-11-13-17-32(2)43(65-8)28-39-21-19-37(7)52(64,69-39)49(61)50(62)56-23-15-14-18-41(56)51(63)68-44(34(4)26-38-20-22-40(45(27-38)66-9)57-30-53-54-55-57)29-42(58)33(3)25-36(6)47(60)48(67-10)46(59)35(5)24-31/h11-13,16-17,25,30-31,33-35,37-41,43-45,47-48,60,64H,14-15,18-24,26-29H2,1-10H3/b13-11+,16-12+,32-17+,36-25+/t31-,33-,34-,35-,37-,38+,39+,40+,41+,43+,44+,45-,47-,48+,52-/m1/s1
    SMILES Code: O=C([[email protected]@](CCCC1)([H])N1C(C([[email protected]@]2(O)[[email protected]](C)CC[[email protected]@](O2)([H])C[[email protected]](OC)/C(C)=C/C=C/C=C/[[email protected]@H](C)C[[email protected]@H](C)C([[email protected]](OC)[[email protected]](O)/C(C)=C/[[email protected]]3C)=O)=O)=O)O[[email protected]]([[email protected]](C)C[[email protected]]4C[[email protected]@H](OC)[[email protected]@H](N5N=NN=C5)CC4)CC3=O

    Synonyms

    A-179578; A179578; A 179578; ABT578; ABT 578; ABT-578; Endeavor; Zotarolimus; 42-deoxy-42-(1H-tetrazol-1-yl)-, (42S)-Rapamycin, 


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    In Vitro

    In Vitro activity: Zotarolimus (ABT-578) is a semi-synthetic analogue of rapamycin, made by substituting a tetrazole ring for the native hydroxyl group at position 42 in rapamycin. Zotarolimus is highly effective in inhibiting both smooth muscle cell and endothelial cell proliferation, with IC50 values of 2.9 nM and 2.6 nM, respectively. Zotarolimus is mechanistically similar to sirolimus in having high-affinity binding to the immunophilin FKBP12 and comparable potency for inhibiting in vitro proliferation of both human and rat T cells. Zotarolimus inhibits Con A-induced human T cells and rat T cells proliferation with IC50 of 7.0 nM and 1337 nM respectively.

     

    Kinase Assay: Binding Affinity to FKBP12: 96-well microtiter plates are first coated with FKBP-12 CMP-KDO synthetase fusion protein at 10 μg/mL, 100 μL/well for 2-3 h, followed by addition of 50 μL/well of buffer A (2% BSA and 0.2% Tween-20 in D-PBS) for 30-60 min. Microtiter plates are then washed three times with buffer B (0.2% Tween in D-PBS, pH adjusted to 7.4). Fifty microlitres of buffer A (for maximum), 20 μM FK506 in buffer A (for background), or various concentrations of zotarolimus (10 pM-1 μM) in buffer A are added to each well followed by addition of 50 μL of A-79397 (an FK506 analogue)-alkaline phosphatase conjugate in buffer A. Microtiter plates are incubated at room temperature for 2-2.5 h followed by three washes with buffer B. About 100 μL of pNPP (p-nitrophenyl-phosphate) in 0.1 M aminomethylpropanol are added to each well and plates are incubated at room temperature for 90-120 min. Absorbance at 405 nM is read using an ELISA plate.

     

    Cell Assay: Cell proliferation is assayed by measuring tritiated thymidine incorporation in vitro. Human coronary artery cells (hCa) are seeded into tissue culture flasks for expansion and applied to 96-well plates at desired density in complete media (5000 hCaSMC; 10 000 hCaEC). After 2 days, complete media is replaced with incomplete media to synchronize cells and induce G0 state. Two days later, incomplete media are removed and replaced with complete media (serum/growth factors) to induce G0 to G1 transition. Complete media also contain drug at desired concentrations to determine its effects on cell proliferation. On day 7, 3H-thymidine is added to cells to monitor DNA synthesis, and cells are harvested after overnight incorporation of radioactivity. After an incubation period of 72 h, 25 μL (1 μCi/well) of 3H-thymidine are added to each well. The cells are incubated at 37°C for 16-18 h to allow for incorporation of 3H-thymidine into newly synthesized DNA and the cells harvested onto 96-well plates containing bonded glass fibre filters . The filter plates are air-dried overnight, MicroScint-20 (25 μL) added to each filter well and counted. Drug activity is determined by the inhibition of 3H-thymidine incorporation into newly synthesized DNA relative to cells grown in complete media.

    In Vivo

    Zotarolimus-eluting stents effectively reduce neointima formation in a 28-day, well-characterized swine model of coronary artery restenosis. Zotarolimus appears effective in preventing neointimal thickening, reducing late loss from 1.03 to 0.62 mm with a 47% reduction in TVF compared with bare metal stents (15.4% with the Driver stent to 8.1% with the Endeavor stent). Zotarolimus is efficacious in suppressing adjuvant DTH, EAE, and cardiac allograft rejection with ED50 values of 1.72, 1.17, and 3.71 mg/kg/day, respectively.

    Animal model

    Male Sprague-Dawley rats

    Formulation & Dosage

    Dissolved in ethanol: propylene glycol: cremophor EL: D5W vehicle (20: 30: 2: 48, by volume); 2.5 mg/kg; i.v. or oral gavage

    References

    Eur Heart J. 2006 Apr;27(8):988-93; J Cardiovasc Pharmacol. 2007 Apr;49(4):228-35.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    Zotarolimus(ABT-578)

    Inhibition of FKBP-12 binding by zotarolimus. Eur Heart J, 2006, 27(8), 988-993.

    Zotarolimus(ABT-578)

    Inhibition of cultured hCaSMC and hCaEC by zotarolimus.

    Zotarolimus(ABT-578)

    Representative histological images of low (×4) and high (×20) power magnification of arteries implanted with zotarolimus-eluting stents (A and C) and control (PC-coated) stents (B and D) after 28 days.


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