3802
G. Wang et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3798–3803
Figure 4. The X-ray crystal structures of thrombin with 4 (A, PDB code 1RIW)19 and trypsin with 6 (B, PDB code 1AQ7).18b The inhibitors are shown in CPK color and protein
shown in purple color. C is the overlay of the active sites of thrombin (purple) and trypsin (green). Residues from trypsin are labeled in white. Residues unique to thrombin are
in yellow. The overlapping residues of thrombin are not labeled.
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tion is quite important and should allow for the design of selective
and potent thrombin inhibitors with optimized P3 and P4 units. A
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simplified residue can be used to replace
an aryl sulfonyl group.
In conclusion, we have synthesized a series of aeruginosin 298-
A analogs in which the Choi is replaced with -proline and the P1
D-Hpla-D-Leu, such as
L
Argol is replaced with various functionalities. Among these tetra-
peptides, several of them exhibit excellent selectivity for thrombin
inhibition over trypsin inhibition. These include cyanobenzyl,
nitrobenzyl, propyl imidazole, cyanobenzyl, C-4-piperidinyl-
methyl, and C-4-pyridinyl-methyl groups at the P1 positions. These
P1 replacements are less basic or neutral, and generally have sim-
pler or smaller groups than Argol or other guanidine containing
units. The SAR data shown here is useful in finding thrombin inhib-
itors that are easy to synthesize and have superior selectivity to-
ward thrombin. Further structure modifications can potentially
lead to the discovery of potent and selective thrombin inhibitors
that are also orally available.
Acknowledgments
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We are grateful to the financial support from American Heart
Association scientist development Grant #0430285N. We also
thank Dr. Xiaoping Nie and Kristopher Williams for their help with
the manuscript.
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Becker, M.; Davis, R.; Spada, A.; Liang, G.; Chu, V.; Brown, K.; Collussi, D.;
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Supplementary data
Supplementary data (the synthesis and characterization of com-
pounds 14–19, 25–39) associated with this article can be found, in
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