Chemical Formula: C21H28BN3O5
Exact Mass: 413.21220, UNII-6IF28942WO;
[(lR)-l-[[(2S,3R)-3-hydroxy-2- [6-phenyl-pyridine-2-carbonyl)amino]-l-oxobutyl]amino]-3-methylbutylboronic acid,
Boronic acid, ((1R)-1-(((2S,3R)-3-hydroxy-1-oxo-2-(((6-phenyl-2-pyridinyl)carbonyl)amino)butyl)amino)-3-methylbutyl)-
In phase 2, multiple mylenoma, Ethical Oncology Science (EOS), licensee
CEP-18770 was discovered through collaboration between Cephalon and Novuspharma/CTI.
Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380, and Cell Therapeutics Europe S.r.l., Via L. Ariosto, 23, I-20091 Bresso, Italy
Cephalon was acquired by Teva in October 2011. In 2013, EOS was acquired by Clovis Oncology.
Chemical Process Research and Development, Teva Branded Pharmaceutical Products R&D Inc., 383 Phoenixville Pike, Malvern, Pennsylvania 19355, United States
CEP-18770 is a reversible P2 threonine boronic acid inhibitor of the chymotrypsin-like activity of the proteasome. Displays anti-multimyeloma (MM) effect.
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Delanzomib, also known as CEP-18770, is An orally bioavailable synthetic P2 threonine boronic acid inhibitor of the chymotrypsin-like activity of the proteasome, with potential antineoplastic activity. Proteasome inhibitor CEP 18770 represses the proteasomal degradation of a variety of proteins, including inhibitory kappaBalpha (IkappaBalpha), resulting in the cytoplasmic sequestration of the transcription factor NF-kappaB; inhibition of NF-kappaB nuclear translocation and transcriptional up-regulation of a variety of cell growth-promoting factors; and apoptotic cell death in susceptible tumor cell populations. In vitro studies indicate that this agent exhibits a favorable cytotoxicity profile toward normal human epithelial cells, bone marrow progenitors, and bone marrow-derived stromal cells relative to the proteasome inhibitor bortezomib. The intracellular protein IkappaBalpha functions as a primary inhibitor of the proinflammatory transcription factor NF-kappaB
New series of dipeptidyl boronate inhibitors of 20S proteasome were identified to be highly potent drug-like candidates with IC50 values of 1.2 and 1.6 nM, respectively, which showed better activities than the drug bortezomib on the market
The potent, selective, and orally bioavailable threonine-derived 20S human proteasome inhibitor that has been advanced to preclinical development, [(1R)-1-[ [ (2S,3R)- 3-hydroxy-2-[ (6-phenylpyridine- 2-carbonyl) amino]-1 -oxobutyl] amino]- 3-methylbutyl] boronic acid (CEP-18770, has been reported
Dorsey BD, Iqbal M, Chatterjee S, Menta E, Bernardini R, Bernareggi A, et al. Discovery of a potent, selective, and orally active proteasome inhibitor for the treatment of cancer. J Med Chem. 2008;51:1068–1072. [PubMed]
Further, the anti-multiple myeloma protea-some inhibitor CEP-18770 enhanced the anti-myeloma activity of bortezomib and melphalan. The combination of anti-multiple myeloma proteasome inhibitor CEP-18770 intravenously and bortezomib exhibited complete regression of bortezomib-sensitive tumours. Moreover, this combination markedly delayed progression of bortezomib-resistant tumours compared to treatment with either agent alone
Development and scale-up of an optimized route to the peptide boronic acid, CEP-18770
Org Process Res Dev 2013, 17(3): 422
CEP-18770 is an unstable peptide boronic acid and an amorphous solid, making it a challenging synthetic target. Process R&D led to a new process that avoided chromatography through crystalline intermediates, increased atom and volume efficiency, provided a chromophore, and gave higher yields and purity. A stable, crystalline diethanolamine adduct was discovered that has the potential to be used as a prodrug.
Compound 8 proved to be a direct substitute for delanzomib in the formulation process. In the first step of the IV formulation process, delanzomib is dissolved in water along with several excipients. Predictably, the delanzomib degrades during this process. It was found that upon dissolution in the lyophilization medium, 8 hydrolyzes to delanzomib,
Discovery of a Potent, Selective, and Orally Active Proteasome Inhibitor for the Treatment of Cancer
The ubiquitin−proteasome pathway plays a central role in regulation of the production and destruction of cellular proteins. These pathways mediate proliferation and cell survival, particularly in malignant cells. The successful development of the 20S human proteasome inhibitor bortezomib for the treatment of relapsed and refractory multiple myeloma has established this targeted intervention as an effective therapeutic strategy. Herein, the potent, selective, and orally bioavailable threonine-derived 20S human proteasome inhibitor that has been advanced to preclinical development, [(1R)-1-[[(2S,3R)-3-hydroxy-2-[(6-phenylpyridine-2-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]boronic acid 20 (CEP-18770), is disclosed.
[(1R)-1-[[(2S,3R)-3-Hydroxy-2-[(6-phenylpyridine-2-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]boronic Acid (20)
Preferred among these compounds is [(lR)-l-[[(2S,3R)-3-hydroxy-2- [6-phenyl-pyridine-2-carbonyl)amino]-l-oxobutyl]amino]-3-methylbutylboronic acid, also known as CEP- 18770, which has the following structure:
NOT SAME BUT SIMILAR
Example E.4 Boronic acid, [(lR)-l-[[(2S,3R)-3-hydroxy-2-[[4-(3-pyridyl)benzoyl]amino]-l- oxobutyI]amino]-3-methyIbutyl].
 A mixture of 4-(pyridin-3-yl)benzamide, N-[(1S,2R)-1-[[[(1R)-1-
[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-l,3,2-benzodioxaborol-2- yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]- of Example D.8.3 (155 mg, 0.283 mmol), 2-methylpropylboronic acid (81 mg, 0.793 mmol) and 2N aqueous hydrochloric acid (0.3 ml) in a heterogeneous mixture of methanol (3 ml) and hexane (3 ml) was stirred at room temperature for 24 hours. The hexane layer was removed and the methanolic layer was washed with fresh hexane (about 5 ml). Ethyl acetate (10 ml) was added to the methanol layer which was then concentrated. The residue was taken up with ethyl acetate and the mixture was concentrated. This step was repeated (2-3 times) until an amorphous white solid was obtained. The solid was then triturated with diethyl ether (5 ml) and the surnatant was removed by decantation. This step was repeated. The residue (126 mg) was combined with the product of a similar preparation (140 mg) and dissolved in ethyl acetate (about 40 ml) and a small amount of methanol (2-3 ml). The solution was washed with a mixture of NaCl saturated solution (7 ml) and 10% NaHCO3 (2 ml). The layers were separated and the aqueous phase was further washed with ethyl acetate (2 x 20 ml). The combined organic phases were dried over sodium sulfate and concentrated. The residue was taken up with ethyl acetate (about 20 ml) and the minimum amount of methanol, and then concentrated to small volume (about 5 ml). The resulting white was collected by filtration and dried under vacuum at 50°C (160 mg, 65% overall yield).
1H NMR (MeOH-d4): 8.90 (IH, s); 8.49 (IH, d, J=4.0); 8.20 (IH, d, J=8.1); 8.06 (2H, d, J=8.1); 7.85 (2H, d, J=8.1); 7.58 (IH, t br., J=6.0); 4.80 (IH, d, J=3.9); 4.40-4.29 (IH, m); 2.78 (IH, t, J=7.5); 1.73-1.61 (IH, m); 1.38 (2H, t, J=6.9); 1.31 (3H, d, J=6.3); 0.94 (6H, d, J=6.31).  Further compounds prepared according to the above procedure for
Example E.4 are reported in Table E-4. Table E-4
E.4.3 IS THE COMPD
D.8.12 Chemical Name: 6-Phenyl-2-pyridinecarboxamide,N-[(lS,2R)-l-[[[(lR)- l-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-
methano-l,3,2-benzodioxaborol-2-yl]-3- methylbutyl]amino]carbonyl]-2-hydroxypropyl]. Analytical Data: Η -NMR (DMSO-d6): 9.20-8.95 (IH, m); 8.76 (IH, d, J=8.55 Hz); 8.26-8.16 (4H, m); 8.12 (IH, t, J= 7.77 Hz); 8.02 (IH, d, J= 7.56 Hz); 7.60-7.47 (4H, m); 5.27 (IH, d, J= 4.97 Hz); 4.50 (IH, dd, J= 4.22 Hz, J= 8.50 Hz); 4.16-4.07 (2H, m); 2.65-2.56 (IH, m); 2.25-2.15 (IH, m); 2.09-1.98 (IH, m); 1.84 (IH, t, J= 5.62 Hz); 1.79- 1.73 (IH, m); 1.73-1.66 (IH, m); 1.66-1.59 (IH, m); 1.40-1.26 (4H, m); 1.23 (7H, d, J= 10.89 Hz); 1.15-1.10 (4H, m); 0.85 (7H, d, J= 6.56 Hz); 0.79 (IH, bs).
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