Synthesis and SAR of Thrombin Inhibitors Incorporating a Novel 4-Amino-Morpholinone Scaffold: Analysis of X-ray Crystal Structure of Enzyme Inhibitor Complex
2001 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623 (print) 1520-4804 (online), Vol. 46, no 19, 3985-4001 p.Article in journal (Refereed) Published
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 α-thrombin. The best candidate in this series of thrombin inhibitors exhibits an in vitro IC50 of 0.130 μM. 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 α-thrombin is discussed.
Place, publisher, year, edition, pages
2001. Vol. 46, no 19, 3985-4001 p.
IdentifiersURN: urn:nbn:se:liu:diva-13362DOI: 10.1021/jm0307990OAI: oai:DiVA.org:liu-13362DiVA: diva2:20482