Highly selective tripeptide thrombin inhibitors

Abstract

Tripeptide aldehydes such as Boc-D-Phe-Pro-Arg-H (51) exhibit potent direct inhibition of thrombin. This distinction offers important insight for the design of more potent and selective serine protease inhibitors which may be useful pharmacological tools and hold promise for development of clinically useful agents. The structure-activity relationships (SAR) on a series of anticoagulant peptides with high selectivity for the enzyme thrombin are discussed. The SAR is centered on a series of di- and tripeptide arginine aldehydes based on the structure of 51. The structural and conformational role of the amino acid residue in position 1 was investigated by substitution with conformationally restricted aromatic amino acids, aromatic acids, and a dipeptide isostere containing the psi[CH2N] amide bond replacement. Many of these peptides demonstrate potent antithrombotic activity along with selectivity toward thrombin, determined by comparison of in vitro inhibitory effects on trypsin, plasmin, factor Xa, and tissue plasminogen activator. Compound 5f, D-1-Tiq-Pro-Arg-H.sulfate is highly active and the most selective tripeptide aldehyde inhibitor of thrombin reported to date.

Applications and Modifications of 1,2,3,4-Tetrahydroisoquinoline-3-Carboxylic Acid (Tic) in Peptides and Peptidomimetics Design and Discovery

“…And combined with other modification, the incorporation of Tic resulted in a new series of compounds with general formula 53 [35]. Moreover, introduction of Tic was proved to be successful in the development of more potent and selective antagonists of bradykinin receptor [36] and in the development of highly selective thrombin inhibitors [37]. As the conformationally restricted Phe, Tic was also incorporated into substance P to assess the structural requirements of tachykinin NK-1 receptor [38,39].…”

Marine Sponges as Pharmacy

“…The process of blood coagulation is triggered by a complex proteolytic cascade that leads to the formation of fibrin. Thrombin is a serine protease that cleaves a peptide fragment from fibrinogen, which then leads to the generation of fibrin, a major component of blood clots (Shuman et al, 1993). Cyclotheonarnide A, represents an unusual class of serine protease inhibitors and is a potential drug for the treatment of thrombosis (Maryanoff et al, 1993).…”

Proteinase inhibitors and activators: strategic targets for therapeutic intervention

“…Several groups have recognized the significance of selectivity for thrombin, compared to the trypsinlike fibrinolytic enzymes for a potential antithrombotic agent [25].…”