(
)
102
M. Gutschow et al.rPharmaceutica Acta HelÕetiae 73 1998 95–103
¨
inhibitory potency of 1–3 for proteinase 3 increased in the
same order as the HLE inhibition. In contrast to the results
with HLE, methyl substitution in 2 and 3 did not affect
deacylation rate, but strongly affected acylation rate. Thus,
compound 3, exhibiting a second-order rate constant for
acylation kon )1=105 My1 sy1, is a highly potent in-
hibitor for human leukocyte proteinase 3.
Acknowledgements
The authors thank Dr. Trevor Payne, Novartis Pharma
Research Basel, for critically reading the manuscript. M.G.
and K.E. would like to thank the ‘Fonds der Chemischen
Industrie’ for financial support.
Proteinase 3 has a primary substrate specificity for
amino acids with small aliphatic residues such as Val or
Ala. One might suspect, that the accelerated acylation of
proteinase 3 by the 5-methyl derivative 3 could be a result
of the accommodation of the methyl substituent at the
primary specificity site, leading to an improved association
of a non-covalent enzyme-inhibitor complex, EI, prior to
the acylation step. Experimentally, the accumulation of EI
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Guetschow, Michael
