incorporation of (NMe)arginine in the 4-benzyloxy-phenylglycine
analogue MB-53, was performed (Table 3). Surprisingly, for
(NMe)arginine derivatives the -methylation of phenylglycine
had no effect, resulting in identical activities of 19 and (R)-28
against both DENV and WNV protease. Introduction of an
(NMe)arginine residue had no influence on the negligible
off-target inhibition of the (Me)phenylglycine derivatives. In
contrast, the N-methylated analogue 29 had significantly lower
activity than the lead compound MB-53: for DENV protease, the
activity was four times lower, and against WNV protease it was
the degradation of the peptidomimetics by pancreatic enzymes was
significantly reduced.
Acknowledgments
We thank Heiko Rudy for measuring HRMS spectra, Natascha
Stefan and Tobias Timmermann for technical support, Tom
Eisenzapf for synthetic help and Konstantin Eckel for synthesizing
the starting material for 1. The present work was supported by the
Deutsche Forschungsgemeinschaft, Grant KL-1356/3-2.
one
order
of
magnitude
less
active.
The
4-benzyloxy-phenylglycine lead compound MB-53 showed some
inhibitory activity against trypsin at a concentration of 50 µM,
which could be suppressed through the N-methylation in 29.
References and notes
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Metabolic stability is an important factor in the development of
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Enzymatic degradation has been observed for other derivatives
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enzymes. 6 9 MB-230, MB-53, (R)-16, 19, 29 and 32 together with
the control substance testosterone were incubated for 120 min at
37°C with rat liver microsomes. Samples were taken at several
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compounds and the peptidomimetics were stable under these
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Next, metabolic stability in the presence of pancreatic enzymes
was determined in analogy to literature conditions.25 MB-230,
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or α-chymotrypsin and aliquots were taken. Rapid degradation of
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(NMe)arginine. Methylation at the C-position of D-phenylglycine
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The -methylation of D-phenylglycine has clear potential to be
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Jakob, Alexander K.M.H.
