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Synthesis and SAR o...
Synthesis and SAR of Thrombin Inhibitors Incorporating a Novel 4-Amino-Morpholinone Scaffold : Analysis of X-ray Crystal Structure of Enzyme Inhibitor Complex
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- Nilsson, Jonas W. (författare)
- Linköpings universitet,Organisk Kemi,Tekniska högskolan
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- Kvarnström, Ingemar (författare)
- Linköpings universitet,Organisk Kemi,Tekniska högskolan
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- Musil, Djordje (författare)
- AstraZeneca R&D, Structural Chemistry Laboratory, Mölndal, Sweden
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- Nilsson, Ingemar (författare)
- AstraZeneca R&D, Structural Chemistry Laboratory, Mölndal, Sweden
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- Samuelsson, Bertil (författare)
- Department of Organic Chemistry, Stockholm University, Stockholm, Sweden and Medivir AB, Huddinge, Sweden
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(creator_code:org_t)
- 2003-08-13
- 2001
- Engelska.
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 46:19, s. 3985-4001
- Relaterad länk:
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http://urn.kb.se/res...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Nyckelord
- NATURAL SCIENCES
- NATURVETENSKAP
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