| Identification | Back Directory | [Name]
MLN9708 | [CAS]
1201902-80-8 | [Synonyms]
MLN9708
CS-1830
Ninlaro)
MLN 9708 analog
MLN-9708 analog
MLN9708;MLN-9708
Ixazomib Citrate
MLN9708,MLN-9708,MLN 9708
MLN 9708 - Ixazomib citrate
MLN9708, 98%, 20S proteasome inhibitor
4-(Carboxymethyl)-2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)-6-oxo-1,3,2-dio
4-(carboxymethyl)-2-(1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)-6-oxo-1,3,2-dioxaborinane-4-carboxylic acid
4-Carboxy-2-[(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-6-oxo-1,3,2-dioxaborinane-4-acetic acid
4-(carboxymethyl)-2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)-6-oxo-1,3,2-dioxaborinane-4-carboxylic acid
1,3,2-Dioxaborinane-4-acetic acid, 4-carboxy-2-[(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-6-oxo-
4-Carboxy-2-[(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-6-oxo-1,3,2-dioxaborinane-4-acetic acid MLN9708 | [Molecular Formula]
C20H23BCl2N2O9 | [MDL Number]
MFCD18251437 | [MOL File]
1201902-80-8.mol | [Molecular Weight]
517.122 |
| Chemical Properties | Back Directory | [Melting point ]
>227°C (dec.) | [density ]
1.47 | [storage temp. ]
Hygroscopic, -20°C Freezer, Under inert atmosphere | [solubility ]
DMSO (Slightly), Methanol (Slightly, Heated, Sonicated) | [form ]
Solid | [pka]
1.92±0.20(Predicted) | [color ]
White to Off-White |
| Hazard Information | Back Directory | [Description]
Ixazomib citrate is a
proteasome inhibitor prodrug for the treatment of multiple
myeloma in patients who have received at least one prior
therapy in combination with lenalidomide and dexamethasone. The drug was developed by Takeda and reversibly
inhibits the protein proteasome subunit β type-5, which is part
of the 20S proteasome complex. Ixazomib citrate (XXIV) is
hydrolyzed quickly in vivo to give the biologically active
compound ixazomib, which presumably is the corresponding
boronic acid variant of XXIV. | [Uses]
MLN-9708 is a novel proteasome?inhibitor. | [Clinical Use]
Highly selective and reversible proteasome inhibitor:
Treatment of multiple myeloma in combination with
lenalidomide and dexamethasone | [Synthesis]
The structure of ixazomib citrate is particularly interesting in
that it is one of the relatively few marketed drugs which feature
a boron atom within its structure (others of note being the
oncology medication bortezomib and the antifungal drug
tavaborole13). The ostensible scale synthetic approach began
with reaction of commercial 2,5-dichlorobenzoyl chloride (188) with glycine in aqueous NaOH to furnish amide
189 in 97% yield as a white crystalline solid. Acid 189 was then
coupled with commercially available 1,3,2-benzodioxaborolane
190 in the presence of TBTU and DIPEA in DMF at low
temperature to give diamide 191, which was used without
purification for the next step. Borane 191 was then deprotected
with (2-methylpropyl)boronic acid in methanolic HCl to
provide trimer 192 in 74% as a white solid. Finally, boroxin
192 was reacted with citric acid in EtOAc to dissociate the
trimer, resulting in ixazomib citrate (XXIV) in 88% yield as a
crystalline solid.
| [Drug interactions]
Potentially hazardous interactions with other drugs Antibacterials: concentration reduced by rifampicin - avoid. Antidepressants: concentration possibly reduced by St John’s wort - avoid. Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin and phenytoin - avoid. Antipsychotics: increased risk of agranulocytosis with clozapine - avoid. | [Metabolism]
Ixazomib citrate is a prodrug that rapidly hydrolyses
under physiological conditions to its biologically active
form, ixazomib. Metabolism is by multiple CYP enzymes
and non-CYP proteins. At clinically relevant ixazomib
concentrations, in vitro studies using human cDNAexpressed cytochrome P450 isozymes indicate that no
specific CYP isozyme predominantly contributes to
ixazomib metabolism and non-CYP proteins contribute
to overall metabolism.
62% of the administered dose is excreted in urine and
22% in the faeces. |
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