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Novel morpholinone-based D-Phe-Pro-Arg mimics as potential thrombin inhibitors: design, synthesis, and X-ray crystal structure of an enzyme inhibitor complex
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
AstraZeneca R&D, Structural Chemistry Laboratory, Mölndal, Sweden.
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2002 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 10, no 6, 1829-1839 p.Article in journal (Refereed) Published
Abstract [en]

A morpholinone structural motif derived from d(+)- and l(−)-malic acid has been used as a mimic of d-Phe-Pro in the thrombin inhibiting tripeptide d-Phe-Pro-Arg. In place of Arg the more rigid P1 truncated p-amidinobenzylamine (Pab) or 2-amino-5-aminomethyl-3-methyl-pyridine have been utilized. The synthetic strategy developed readily delivers these novel thrombin inhibitors used to probe the α-thrombin inhibitor binding site. The best candidate in this series of thrombin inhibitors exhibits an in vitro IC50 of 720 nM. The X-ray crystal structure of this candidate co-crystallized with α-thrombin is discussed.

Place, publisher, year, edition, pages
2002. Vol. 10, no 6, 1829-1839 p.
National Category
Engineering and Technology
Identifiers
URN: urn:nbn:se:liu:diva-47039DOI: 10.1016/S0968-0896(02)00023-8OAI: oai:DiVA.org:liu-47039DiVA: diva2:267935
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2012-12-06
In thesis
1. Design and synthesis of inhibitors that target the serine protease thrombin, the malarial aspartyl proteases plasmepsin I and II, and the hepatitis C virus NS3 serine protease
Open this publication in new window or tab >>Design and synthesis of inhibitors that target the serine protease thrombin, the malarial aspartyl proteases plasmepsin I and II, and the hepatitis C virus NS3 serine protease
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis addresses the design, synthesis, and structure-activity relationships of protease inhibitors that target the serine protease thrombin, the malarial aspartic proteases plasmepsin I and II, and the hepatitis C virus (HCV) NS3 serine protease. Furthermore, the backgrounds of each of the three types of diseases in question are discussed in detail, and consideration is given as to why it is assumed that inhibition of the mentioned proteases will help prevent or cure cardiovascular diseases, malaria, and hepatitis C.

The enzyme thrombin is a key factor in the blood coagulation cascade, and it is believed that inhibition of thrombin can have great implications in the treatment and prevention of a number of cardiovascular conditions, such as deep venous and arterial thrombosis, pulmonary embolism, and unstable angina. In the present research, we synthesized a series of potential thrombin inhibitors that incorporate novel morpholinonebased scaffolds derived from D(+)- and L(-)-malic acid mimicking proline in the thrombin-inhibiting tripeptide D-Phe-Pro-Arg. The most effective inhibitors in this series of compounds have IC50 values in the nanomolar to low micromolar range. We used the X-ray crystal structure to study the interactions between the best inhibitor and the active site of the enzyme.

Malaria is the most serious parasitic disease in the world, annually affecting approximately 500 million people and killing as many as two million. The malaria parasites degrade hemoglobin in the red blood cells as a source of the amino acids that are necessary for growth and maturation. A number of protease enzymes are involved in the breakdown of hemoglobin, and it is believed that the aspartic proteases plasmepsin I and II play important roles in this process. We developed a number of highly potent inhibitors of plasmepsins I and II that encompass modified statine motifs. In this endeavor, solid-phase combinatorial chemistry was used to synthesize libraries of compounds. The most promising compounds obtained from these libraries were further optimized by performing Suzuki couplings to yield inhibitors with Ki values in the picomolar range. Detailed information on the binding properties of these compounds was obtained by studying the X-ray crystal structure of an enzyme-inhibitor complex.

Hepatitis C is predominantly a chronic disease that afflicts 3% of the world's population, or about 170 million people. The virus, which in the long run leads to cirrhosis and liver cancer, is the leading indication for liver transplantation in the developed world. The HCV NS3 serine protease is essential for viral replication, because it is involved in processing the non-structural portion of a virally encoded polyprotein into functional enzymes. Thus, the NS3 protease has been recognized as one of the most important targets for the development of drugs used to fight HCV. We synthesized several potent and promising HCV NS3 inhibitors comprising a novel trisubstituted cyclopentane moiety as an N-acyl-(4R)-hydroxyproline bioisostere. By systematically optimizing the substituents on this scaffold, we were able to identify very promising inhibitors in the nanomolar range.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2005. 78 p.
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 981
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-29722 (URN)15118 (Local ID)91-85457-57-4 (ISBN)15118 (Archive number)15118 (OAI)
Public defence
2005-11-25, Hörsal Planck, Fysikhuset, Campus Valla, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-12-06

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Dahlgren, AndersJohansson, Per-OlaKvarnström, Ingemar

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