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Figure 3. Connolly surface map of the X-ray structure of a-thrombin±
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An examination of the crystal structure of the a-throm-
bin±2 complex reveals the importance of the functional,
topological, and stereochemical features of the designed
inhibitor (Figs 2 and 3). The choice of a slightly convex
indolizidinone motif with the b-hydrogen at C-6 based
on modeling studies is also validated. Unlike many
other thrombin inhibitors, compound 2 does not incor-
porate a `serine trap' as a critical functional motif for
activity. The presence of a tertiary a-hydroxy lactam
group rather than an amine as a H-donor±acceptor unit
for Gly 216 is another noteworthy functional feature.
Further re®nements can now be considered in the light
of these results, and they will be reported in due course.
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We thank NSERCC for a scholarship to E. B. and
AstraZeneca Molndal for generous ®nancial support
through the Medicinal Chemistry Chair Program, and
Dr. Michel Simard for X-ray structure analyses of
compounds 12, 15 and 16. We thank Dr. Olle Karlsson
for the synthesis of some amidine reagents, and Dr. Jan
Christer Ulvinge and co-workers, AstraZeneca R&D,
Molndal for the biological tests.
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