Synthesis and SAR of thrombin inhibitors incorporating a novel 4-amino-morpholinone sscaffold: analysis of X-ray crystal structure of enzyme inhibitor complex |
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Authors: | Nilsson Jonas W Kvarnström Ingemar Musil Djordje Nilsson Ingemar Samulesson Bertil |
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Affiliation: | Department of Chemistry, Link?ping University, S-581 83 Link?ping, Sweden. |
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Abstract: | A 4-amino-2-carboxymethyl-3-morpholinone structural motif derived from malic acid has been used to mimic d-Phe-Pro in the thrombin inhibiting tripeptide d-Phe-Pro-Arg. The arginine in D-Phe-Pro-Arg was replaced by the more rigid P1 truncated p-amidinobenzylamine (Pab). These new thrombin inhibitors were used to probe the inhibitor binding site of alpha-thrombin. The best candidate in this series of thrombin inhibitors exhibits an in vitro IC50 of 0.130 microM. Interestingly, the stereochemistry of the 4-amino-2-carboxymethyl-3-morpholinone motif is reversed for the most active compounds compared to that of a previously reported 2-carboxymethyl-3-morpholinone series. The X-ray crystal structure of the lead inhibitor cocrystallized with alpha-thrombin is discussed. |
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