Ixazomib

ChEBI: A glycine derivative that is the amide obtained by formal condensation of the carboxy group of N-(2,5-dichlorobenzoyl)glycine with the amino group of [(1R)-1-amino-3-methylbutyl]boronic acid. The active metabolite of ixa omib citrate, it is used in combination therapy for treatment of multiple myeloma.

Ixazomib is a glycine derivative that is the amide obtained by formal condensation of the carboxy group of N-(2,5-dichlorobenzoyl)glycine with the amino group of [(1R)-1-amino-3-methylbutyl]boronic acid. The active metabolite of ixazomib citrate, it is used in combination therapy for treatment of multiple myeloma. It has a role as an apoptosis inducer, an orphan drug, a proteasome inhibitor, a drug metabolite and an antineoplastic agent. It is a member of benzamides, a dichlorobenzene, a glycine derivative and a member of boronic acids.|Ixazomib a second generation proteasome inhibitor (PI) and the first oral PI approved by the FDA in November 2015 for multiple myeloma treatment in combination with 2 other therapies (lenalidomide and dexamethasone) for patients who have received at least 1 prior therapy. It was found to have similar efficacy to bortezomib (the first PI approved for multiple myeloma therapy) in the control of myeloma growth and prevention of bone loss. Ixazomib citrate is marketed by Takeda Pharmaceuticals under the brand name Ninlaro, which is a prodrug that becomes quickly converted to its active metabolite, ixazomib, after administration.|Ixazomib is a Proteasome Inhibitor. The mechanism of action of ixazomib is as a Proteasome Inhibitor.|Ixazomib is a small molecule proteasome inhibitor that is used in combination with other antineoplastic agents to treat refractory multiple myeloma. Ixazomib is associated with a low rate of serum enzyme elevations during treatment and to rare instances of clinically apparent, acute liver injury.|Ixazomib is an active metabolite of MLN9708, a second generation, boron containing peptide proteasome inhibitor (PI) with potential antineoplastic activity. Ixazomib binds to and inhibits the 20S catalytic core of the proteasome, thereby blocking the targeted proteolysis normally performed by the proteasome, which results in an accumulation of unwanted or misfolded proteins; disruption of various cell signaling pathways may follow, resulting in the induction of apoptosis. Compared to first generation PIs, second generation PIs may have an improved pharmacokinetic profile with increased potency and less toxicity. Proteasomes are large protease complexes that degrade unneeded or damaged proteins that have been ubiquinated.

The pinanediol boronate ester (5 g) of compound of formula Tb was mixed with amixture of concentrated hydrochloric acid (5 mL) and boric acid (1.9 g) indiisopropyl ether (100 mL) at ambient temperature. The reaction mixture wasstirred for 5 hours and solid was filtered and washed with diisopropyl ether (25mL). The isolated solid was dried under vacuum to obtain Txazomib. (Yield: 86.5percent)Compound VI (317 mg, 0.49 mmol) was dissolved in 3 mL of MeOH and isobutylboronic acid (247 mg, 2.43 mmol), n-hexane (3 mL) and IN HCl (1.2 mL, 1.2 mmol) were added and the reaction stirred overnight.TLC detection reaction, n-hexane The methanol phase was washed once with MeOH (2 x 3 mL) and n-hexane (3 mL). The methanol, CH2Cl2 (2 x 2 mL) The aqueous phase was washed twice with saturated brine (3 x 5 mL) to the aqueous phase. The solvent was distilled off under reduced pressure and separated by column chromatography A yield of 76.5percent was obtained from 193 mg of pure product.Dissolve citric acid (292 mg, 1.52 mmol) in 8 mL of ethyl acetate, warm to 74 C, add intermediate IV (500 mg, 1.4 mmol) dissolved in 1.5 mL of ethyl acetate, and slowly cool to 60 C , React for 3 h, and then slowly lower the temperature to 25 C. and stir overnight. It was then filtered with suction and the filter cake was dried under vacuum to obtain 557 mg of pure product with a yield of 94%.Compound IIi (50 mg), D4-citric acid (66 mg) was dissolved in 4 mL of butyl acetate, and the reaction was heated at 90 °C for 2 h, allowed to cool slowly to room temperature, and stirring was continued for 12 h, and the white solid was filtered. The ethyl acetate was washed to give the white solid compound Io (53 mg).The compound IIm (50 mg), D2-citric acid (66 mg) was dissolved in 4 mL of butyl acetate, and the reaction was heated at 90 °C for 2 h, allowed to cool slowly to room temperature, and stirring was continued for 12 h, and the white solid was filtered. The ethyl acetate was washed to give a white solid compound (51 mg).The pinanediol boronate ester (5 g) of compound of formula Tb was mixed with amixture of concentrated hydrochloric acid (5 mL) and boric acid (1.9 g) indiisopropyl ether (100 mL) at ambient temperature. The reaction mixture wasstirred for 5 hours and solid was filtered and washed with diisopropyl ether (25mL). The isolated solid was dried under vacuum to obtain Txazomib. (Yield: 86.5percent)

Molecular Weight:361.0
Hydrogen Bond Donor Count:4
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:7
Exact Mass:360.0814926
Monoisotopic Mass:360.0814926
Topological Polar Surface Area:98.7
Heavy Atom Count:23
Complexity:412
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes