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Synthesis and SAR of Thrombin Inhibitors Incorporating a Novel 4-Amino-Morpholinone Scaffold: Analysis of X-ray Crystal Structure of Enzyme Inhibitor Complex
Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
AstraZeneca R&D, Structural Chemistry Laboratory, Mölndal, Sweden.
AstraZeneca R&D, Structural Chemistry Laboratory, Mölndal, Sweden.
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2001 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. 46, no 19, 3985-4001 p.Article in journal (Refereed) Published
Abstract [en]

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.
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:liu:diva-13362DOI: 10.1021/jm0307990OAI: oai:DiVA.org:liu-13362DiVA: diva2:20482
Available from: 2005-09-21 Created: 2005-09-21 Last updated: 2009-05-28
In thesis
1. Design, Synthesis and Characterization of Small Molecule Inhibitors and Small Molecule: Peptide Conjugates as Protein Actors
Open this publication in new window or tab >>Design, Synthesis and Characterization of Small Molecule Inhibitors and Small Molecule: Peptide Conjugates as Protein Actors
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes different aspects of protein interactions. Initially the function of peptides and their conjugates with small molecule inhibitors on the surface of Human Carbonic Anhydrase isoenzyme II (HCAII) is evaluated.

The affinities for HCAII of the flexible, synthetic helix-loop-helix motif conjugated with a series of spacered inhibitors were measured by fluorescence spectroscopy and found in the best cases to be in the low nM range. Dissociation constants show considerable dependence on linker length and vary from 3000 nM for the shortest spacer to 40 nM for the longest with a minimum of 5 nM for a spacer with an intermediate length. A rationale for binding differences based on cooperativity is presented and supported by affinities as determined by fluorescence spectroscopy. Heteronuclear Single Quantum Correlation Nuclear Magnetic Resonance (HSQC) spectroscopic experiments with 15N-labeled HCAII were used for the determination of the site of interaction.

The influence of peptide charge and hydrophobicity was evaluated by surface plasmon resonance experiments. Hydrophobic sidechain branching and, more pronounced, peptide charge was demonstrated to modulate peptide – HCAII binding interactions in a cooperative manner, with affinities spanning almost two orders of magnitude.

Detailed synthesis of small molecule inhibitors in a general lead discovery library as well as a targeted library for inhibition of α-thrombin is described. For the lead discovery library 160 members emanate from two N4-aryl-piperazine-2-carboxylic acid scaffolds derivatized in two dimensions employing a combinatorial approach on solid support.

The targeted library was based on peptidomimetics of the D-Phe-Pro-Arg showing the scaffolds cyclopropane-1R,2R-dicarboxylic acid and (4-amino-3-oxo-morpholin-2-yl)- acetic acid as proline isosters. Employing 4-aminomethyl-benzamidine as arginine mimic and different hydrophobic amines and electrophiles as D-phenylalanine mimics resulted in 34 compounds showing IC50 values for α-thrombin ranging more than three orders of magnitude with the best inhibitor showing an IC50 of 130 nM. Interestingly, the best inhibitors showed reversed stereochemistry in comparison with a previously reported series employing a 3-oxo-morpholin-2-yl-acetic acid scaffold.

Place, publisher, year, edition, pages
Institutionen för fysik, kemi och biologi, 2005
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 960
Keyword
Synthetic receptor, Peptide inhibitor conjugate, Peptide protein surface interactions, General Lead Discovery Library, Combinatorial Chemistry, Solid Phase Chemistry, Targeted Library, Thrombin inhibitor, Fluorescence, Surface Plasmon Resonance
National Category
Organic Chemistry
Identifiers
urn:nbn:se:liu:diva-3943 (URN)91-85457-00-0 (ISBN)
Public defence
2005-09-16, Planck, Fysikhuset, Campus Valla, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2005-09-21 Created: 2005-09-21 Last updated: 2009-03-06

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Nilsson, Jonas W.Kvarnström, Ingemar

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