1201902-80-8

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.

MLN-9708 is a novel proteasome?inhibitor.

Highly selective and reversible proteasome inhibitor:
Treatment of multiple myeloma in combination with lenalidomide and dexamethasone

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.

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.

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.