Development of Macrocyclic Peptides Containing Epoxyketone with Oral Availability as Proteasome Inhibitors

Macrocyclization
has been frequently utilized for optimizing peptide
or peptidomimetic-based compounds. In an attempt to obtain potent,
metabolically stable, and orally available proteasome inhibitors,
30 oprozomib-derived macrocyclic peptides with structural diversity
in their N-terminus and linker were successively
designed and synthesized for structure–activity relationship
(SAR) studies. As a consequence, the macrocyclic peptides with N-methyl-pyrazole (24p, 24x),
imidazole (24t), and pyrazole (24v) as their
respective N-termini exhibited favorable in vitro
activity and metabolic stability, which translated into their potent
in vivo proteasome inhibitory activity after oral administration.
In particular, compound 24v, as the most distinguished
one among this series, displayed excellent chymotrypsin-like (ChT-L,
β5) inhibitory potency (IC50 = 16 nM), low nanomolar
antiproliferative activity against all three of the tested cell lines,
and superior metabolic stability in mouse liver microsome (MLM), as
well as favorable inhibition against ChT-L compared to that of oprozomib
in BABL/c mice following po administration at a comparatively low
dose, thereby representing a promising candidate for further development.