1038
R. Bihovsky et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1035–1038
Figure 2. SAR of representative analogues illustrating enhanced sensitivity of a-ketoamide versus aldehydes to structural changes.
For example, 8c, 11c and 11k were essentially inactive
against cathepsin B and chymotrypsin (IC50=1–10 mM).
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Josef, K.; Wells, G. J.; Tripathy, R.; Iqbal, M.; Bihovsky,
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It should be noted that we as well as others have repor-
ted on the generally lower potency and relatively nar-
rower structural constraints of a-ketoamides versus
their aldehyde counterparts, and benzothiazines are no
exception in this regard. As shown in Figure 2, both
chloro and alkoxy substituents on the benzene ring, or
the presence of either a single or double bond on the
thiazine ring, were quite potent in the aldehyde series
whereas their a-ketoamide congeners were significantly
less potent and more sensitive to such changes. It is
possible that the generally higher electrophilicity of
aldehydes over a-dicarbonyl groups, along with the
apparent strict P01–P03 structural requirements for effi-
cient ligation in this region, conspire to make a-dicar-
bonyl analogues a significantly greater challenge to
achieving comparable in-vitro potency.
In this paper, we have described a series of potent 3,4-
dihydro-1,2-benzothiazine 1,1-dioxide a-ketoamide
calpain I inhibitors. Further exploration of P0-spanning
sulfonamide groups resulted in analogues rivaling the
potency observed with their aldehyde counterparts.
Molt-4 cell activity and brain levels of key analogues
were comparable to other peptides and mimetics
studied previously. Future progress in this area will
hinge on advances in improving solubility and
consequent formulatability.
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Thanks are extended to Drs. Sankar Chatterjee and
Mark A. Ator for useful discussions and suggestions.
We are also grateful to Donna Bozyczko-Coyne,
Shobha E. Senadi, Teresa M. O’Kane, Beth Ann
McKenna, and Satish Mallya for conducting biochemical
and whole-cell assays.
References and notes
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