Definition
ChEBI: A synthetic tetrapeptide consisting of morpholin-4-acetyl, L-2-amino-4-phenylbutanoyl, L-leucyl and L-phenylalanyl residues joined in sequence with the C-terminus connected to the amino group of (2
Originator
Proteolix Inc. (United States)
Clinical Use
Carfilzomib is an irreversible inhibitor of the chymotrypsin-like protease in the proteasome and was
approved in the U.S. for the treatment of multiple myeloma. Carfilzomib was discovered by
Proteolix which was later acquired by Onyx Therapeutics who completed the development of this drug.
Carfilzomib is also undergoing clinical evaluation for additional oncology indications such as relapsed
solid tumors, lymphoma, prolymphocytic leukemia, acute myeloid leukemia and acute lymphocytic leukemia.
Synthesis
Carfilzomib is an analog of the natural product epoxomicin which was first synthesized in
the laboratories of Professor Crews at Yale University. Subsequent development of the SAR led to the
discovery of YU-101 in which 3 of the amino acids of this pentapeptide were modified to improve the
potency of the molecule. After licensing the molecule to Proteolix, the introduction of the morpholino
group was found to improve the solubility of the drug while maintaining efficient interaction with the
target. The most scalable route to carfilzomib closely resembles the original route developed toward
epoximicin and is described herein.
The synthesis was initiated with the amide coupling of phenyl alanine methyl ester (53) and N-Boc
leucine (54) using standard coupling reagents to afford dipeptide 55 in high yield the Scheme below. Acidic
removal of the amine protecting group followed by a second amide coupling reaction with N-Boc
homophenyl alanine provided tripeptide 56 in 85% yield for the two steps. Acidic removal of the amine
protecting group followed by acylation with chloroacetyl chloride provided β-chloro amide 57 in 67%
yield. Reaction of 57 with morpholine in the presence of catalytic amounts of potassium iodide
followed by saponification of the methyl ester with lithium hydroxide provided acid 58 in 87% yield for
the two steps. Amide coupling between acid 58 and keto-epoxyamine 59 (whose preparation is
described in the scheme below) using HOBT as the coupling reagent followed by recrystallization of the
resulting product ultimately gave carfilzomib (IX) in 75% yield.
Keto-epoxyamine 59 was prepared from N-Boc leucine (54) as described in the Scheme below. Reaction of
54 with isobutyl chloroformate followed by N,O-dimethylhydroxylamine provided Weinreb amide 60 in
94% yield. Grignard addition of isopropenylmagnesium bromide 60 provided enone 62 in 81% yield.
Epoxidation of 62 with calcium hypochlorite provided a mixture of epoxides giving 41% yield of the desired isomer (presumably isolated by chromatography), and subsequent treatment with TFA liberated
the amine, providing the TFA salt of ketoepoxy amine 59 in 92% yield.
Drug interactions
Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine - increased risk
of agranulocytosis.
Metabolism
Carfilzomib was rapidly and extensively metabolised
by mainly peptidase cleavage and epoxide hydrolysis.
Cytochrome P450 mediated mechanisms played a minor
role in overall carfilzomib metabolism. The metabolites
have no known biologic activity.
storage
Desiccate at -20°,unstable in solution, ready to use.
References
1) Bennett and Kirk (2008)?Development of proteasome inhibitors in oncology and autoimmune diseases; Curr. Opin. Drug Disc. Dev.?11?616
2) Hanada?et al.?(1992),?Epoxomicin, a new antitumor agent of microbial origin; J. Antibiot. (Tokyo),?45?174
3) Demo?et al. (2007)?Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome; Cancer Res.?67?6383
4) Kuhn?et al. (2007),?Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma; Blood,?110?328
;