Oprozomib

Description

ONX 0912 is an orally bioavailable proteasome inhibitor. It potently targets the chymotrypsin-like activity of the 20S proteasome subunits β5 and LMP7 (IC₅₀s = 36 and 82 nM, respectively). ONX 0912 inhibits the growth of multiple myeloma cells at nanomolar concentrations while not decreasing the viability of normal peripheral blood mononuclear cells at 1 μM. It blocks the growth of xenografted human multiple myeloma cells in mice when given orally. ONX 0912 has potential applications in certain types of cancer as well as other diseases that require proteasome activity.

Uses

Oprozomib is the second class of proteasome inhibitors with higher specificities and reduced toxicities, against head and neck squamous cell carcinoma.

Synthesis

1148157-29-2

1010136-49-8

935888-69-0

Synthesis of N-((S)-3-methoxy-1-((S)-3-methoxy-1-((S)-1-((R)-2-methoxy-2-yl)-1-oxo-3-phenylpropan-2- yl)amino)-1-oxopropan-2-yl) from compound (CAS:1148157-29-2) and compound (CAS:1010136-49-8) (Amino)-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide was prepared in the general steps as follows: in an inert atmosphere, Compound H (1.2 eq.), Compound G (1.0 eq.), H1311J (1.2 eq.), HOST (1.2 eq.), and N-methylpyrrolidinone (8 L/kg of Compound G) were added to a dry flask at 23°C and stirred until completely dissolved. Subsequently, the reaction mixture was cooled to -5 to 0 °C and diisopropylethylamine (2.1 eq.) was slowly added over 15 min while the internal reaction temperature was controlled below 0 °C. The reaction mixture continued to be stirred at 0 °C. The reaction mixture was poured into 8% sodium bicarbonate solution (40 L/kg of compound G) to precipitate crude compound 1 and the suspension was stirred at 20 to 25 °C for 12 hours. Afterwards, it was stirred at 0 to 5°C for 1 h. The white solid was obtained by filtration and washed with water (5 L/kg compound G). The white solid was then slurried in water (15 L/kg) at 20 to 25°C for 3 h. The white solid was filtered and washed with water (5 L/kg Compound G) and isopropyl acetate (2 x 2 L/kg Compound G). The white solid was dried under vacuum at 45 °C to constant weight to give crude compound 1 in 65% yield and 97.2% HPLC purity. Crude compound 1 was completely dissolved in isopropyl acetate (20 L/kg crude compound 1) by heating to 85 °C, and a clarified solution was obtained by thermal filtration to remove particulate matter before heating to 85 °C. The clarified solution was cooled to 65°C at a rate of 10°C/hour and crystalline species were added. When significant crystallization was observed, cooling was continued to 20°C at a rate of 10°C/hour and the suspension was stirred at 20°C for 6 hours, followed by stirring at 0 to 5°C for at least 2 hours. Filtration and rinsing with isopropyl acetate (1 L/kg crude compound 1) was performed and the purified compound 1 was dried under vacuum at 45 °C for at least 24 h to constant weight in a final yield of 87% and HPLC purity of 97.2%.

in vivo

Enzyme inhibitor

This orally active inhibitor (FW = 532.61 g/mol; CAS 935888-69-0; Solubility: 105 mg/mL DMSO, <1 mg/mL H2O), also known as ONX 0912 and O-methyl-N-[(2-methyl-5-thiazolyl)carbonyl]-L-seryl-O-methyl-N-[(1S)-2-[(2R)-2-methyl-2-oxiranyl]-2-oxo-1-(phenylmethyl)-ethyl]-Lserinamide, selectively targets the chymotrypsin-like (CT-L) activity of 20S proteasome β5 (IC50 = 36 nM) and 20S proteasome LMP7 (IC50 = 82 nM). In animal tumor model studies, ONX 0912 significantly reduced tumor progression and prolonged survival. Immununostaining of multiple myeloma tumors from ONX 0912-treated mice showed growth inhibition, apoptosis, and a decrease in associated angiogenesis. Oprozomib is distinct from carfilzomib, even though the same chemistry was employed to selectively target the proteasome. Oprozomib is under development as an oral therapy for hematologic malignancies, including multiple myeloma, and for patients with recurrent or refractory solid tumors (See also Carfilzomib).

target

20S proteasome β5

References

[1] Patent: US2014/113855, 2014, A1. Location in patent: Paragraph 0279; 0305; 0306; 0307; 0308
[2] Patent: US2018/78532, 2018, A1. Location in patent: Paragraph 0233; 0242; 0249; 0250; 0251; 0252; 0253; 0254
[3] Patent: US2010/240903, 2010, A1. Location in patent: Page/Page column 14
[4] Patent: US2018/161279, 2018, A1. Location in patent: Paragraph 0482-0483; 0492-0495; 0496-0499