Change search
ReferencesLink to record
Permanent link

Direct link
Design, synthesis and biological evaluation of thrombin inhibitors based on a pyridine scaffold.
Umeå University, Faculty of Science and Technology, Chemistry.
Show others and affiliations
2007 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, Vol. 5, no 16, 2599-605 p.Article in journal (Other academic) Published
Abstract [en]

A series of 2,4-disubstituted pyridine derivatives has been designed, synthesised and evaluated as thrombin inhibitors. A Grignard exchange reaction was used to introduce various benzoyl substituents in position 4 of the pyridine ring, where they serve as P3 residues in binding to thrombin. In position 2 of the pyridine ring, a para-amidinobenzylamine moiety was incorporated as P1 residue by an SNAr reaction using ammonia as nucleophile followed by a reductive amination. A crystal structure obtained for one of the compounds in the active site of thrombin revealed that the basic amidine group of the inhibitor was anchored to Asp 189 at the bottom of the S1 pocket. A comparison with melagatran, bound in the active site of thrombin, revealed a good shape match but lack of hydrogen bonding possibilities in the S2–S3 region for the thrombin inhibitors reported in this study.

Place, publisher, year, edition, pages
2007. Vol. 5, no 16, 2599-605 p.
URN: urn:nbn:se:umu:diva-5964DOI: doi:10.1039/b705344dPubMedID: 18019535OAI: diva2:145632
Available from: 2007-12-04 Created: 2007-12-04 Last updated: 2009-08-27Bibliographically approved
In thesis
1. Synthesis of β-turn and pyridine based peptidomimetics
Open this publication in new window or tab >>Synthesis of β-turn and pyridine based peptidomimetics
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Despite the unfavorable pharmacokinetic properties associated with peptides, they are still of great interest in drug development due to a multitude of interesting biological functions. The development of peptidomimetics strives to maintain or improve the biological activity of a peptide concurrently with removing the unwanted properties. This thesis describes two synthetic approaches to peptidomimetics with particular emphasis on secondary structure mimetics.

First the design, synthesis and evaluation of two beta-turn mimetics incorporated in the endorphin Leu-enkephalin is presented. The beta-turn mimetics were stabilized by replacement of the intramolecular hydrogen bond with an ethylene bridge, and the amide bond between Tyr and Gly was replaced with an ether linkage. Linear analogues of the two mimetics were also synthesized. The peptidomimetics and their linear analogues were evaluated in a competitive binding assay at two opiate receptors, my and delta. One of the cyclized beta-turn mimetics was found to be a delta receptor antagonist with an IC50 value of 160 nM.

Second a synthetic strategy to a beta-strand mimetic using 2-fluoro-4-iodopyridine as scaffold is described. The synthesis involved a Grignard exchange reaction on the pyridine scaffold using an amino acid derivative as electrophile followed by an SNAr reaction using an amine as nucleophile. The synthesis of a tripeptidomimetic of Leu-Gly-Gly and attempts to introduce chiral building blocks at the C-terminal, as well as studies towards elongated mimetics are presented.

Two additional studies deal with the synthesis of two classes of potential thrombin inhibitors based on the pyridine scaffold. The first class contain pyridine as central fragment (P2 residue) substituted with a para-amidinobenzylamine group as P1 residue and various benzoyl groups as P3 residues. Three potential thrombin inhibitors were synthesized and found to be microM inhibitors in an enzymatic assay. In the second class, the pyridine ring serves as P3 residue. This class also lacks a strongly basic group in the P1 position. A small library of eight compounds were synthesized and evaluated in the enzymatic assay. Unfortunately, these compounds lacked inhibitory activity.

Place, publisher, year, edition, pages
Umeå: Kemi, 2007. 90 p.
Peptidomimetics, beta-turn, beta-strand, pyridine scaffold, Grignard exchange reaction, SNAr reaction, thrombin inhibitor, Leu-enkephalin.
National Category
Organic Chemistry
urn:nbn:se:umu:diva-1104 (URN)978-91-7264-305-5 (ISBN)
Public defence
2007-05-26, KB3A9, KBC, Umeå Universitet, Umeå, 10:00 (English)
Available from: 2007-05-03 Created: 2007-05-03 Last updated: 2009-08-27Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Kihlberg, Jan
By organisation
In the same journal
Organic and biomolecular chemistry

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 29 hits
ReferencesLink to record
Permanent link

Direct link