Active Site-Directed Thrombin Inhibitors: α-Hydroxyacyl-Prolyl-Arginals, New Orally Active Stable Analogues of D-Phe-Pro-Arg-H

Bajusz, S.; Barabás, Éva; Fauszt, I; Fehér, A.; Horváth, Gyula; Juhász, Attila; Szabó, Gabriella; Széll, E.

doi:10.1055/s-2007-999014

Cited by 3 publications

(3 citation statements)

References 2 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To examine their P3 structural preferences, granzymes A and K, mast cell tryptase, and trypsin were investigated with analogues of RCO-AA-Ala-D,L-(4-AmPhGly) P (OPh) 2 . Several N-blocked-Pro-(4-AmPhGly) P (OPh) 2 analogues that were developed as thrombin inhibitors based on current literature [49][50][51] were found to be excellent inhibitors for the enzymes in this study. The derivative Ph-CH 2 -SO 2 -Gly-Pro-(4-AmPhGly) P (OPh) 2 (43) was the most potent of this series against granzyme A (k obs /[I] ) 3650 M -1 s -1 ).…”

Section: Resultsmentioning

confidence: 85%

Synthesis and Evaluation of Diphenyl Phosphonate Esters as Inhibitors of the Trypsin-like Granzymes A and K and Mast Cell Tryptase

Jackson

Fraser

et al. 1998

J. Med. Chem.

View full text Add to dashboard Cite

Thirty-six new amino acid and peptidyl diphenyl phosphonate esters were synthesized and evaluated to identify potent and selective inhibitors for four trypsin-like proteases: lymphocyte granzymes A and K, human mast cell tryptase, and pancreatic trypsin. Among five Cbz derivatives of Lys and Arg homologues, Z-(4-AmPhe)P(OPh)2 is the most potent inhibitor for granzyme A, and Z-LysP(OPh)2 is the best inhibitor for granzyme K, mast tryptase, and trypsin. The amidino P1 residue D,L-(4-AmPhGly)P(OPh)2 was utilized in a series of compounds with several different N-protecting groups and systematic substitutions at P2 in Cbz-AA derivatives and at P3 in Cbz-AA-Ala derivatives. Generally, these phosphonates inhibit granzyme A and trypsin more potently than granzyme K and tryptase. The P2 Thr and Ala dipeptide phosphonates, Cbz-AA-(4-AmPhGly)P(OPh)2, are the most potent inhibitors for granzyme A, and Cbz-Thr-(4-AmPhGly)P(OPh)2 (kobs/[I] = 2220 M-1 s-1) was quite specific with much lower inhibition rates for granzyme K and trypsin (kobs/[I] = 3 and 97 M-1 s-1, respectively) and no inhibition with tryptase. The most effective inhibitor of granzyme A was Ph-SO2-Gly-Pro-(4-AmPhGly)P(OPh)2 with a second-order rate constant of 3650 M-1 s-1. The most potent inhibitor for granzyme K was 3, 3-diphenylpropanoyl-Pro-(4-AmPhGly)P(OPh)2 with a kobs/[I] = 1830 M-1 s-1; all other phosphonates inhibited granzyme K weakly (kobs/[I] < 60 M-1 s-1). Human mast cell tryptase was inhibited slowly by these phosphonates with Cbz-LysP(OPh)2 as the best inhibitor (kobs/[I] = 89 M-1 s-1). The overall results suggest that scaffolds of Phe-Thr-(4-AmPhe) and Phe-Pro-Lys will be useful to create selective phosphonate inhibitors for granzymes A and K, respectively, and that P4 substituents offer opportunities to further enhance selectivity and reactivity.

show abstract

Section: Resultsmentioning

confidence: 85%

Synthesis and Evaluation of Diphenyl Phosphonate Esters as Inhibitors of the Trypsin-like Granzymes A and K and Mast Cell Tryptase

Jackson

Fraser

et al. 1998

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

“…Many of these are active site-directed small inhibitors and are classified into two groups: the substrate type inhibitors and the nonsubstrate type. (D-Phe)-Pro-Arg-H (Bajusz et al, 1990), Ac-(D-Phe)-Pro-boroArg-OH (Kettner et al, 1990), and N-methyl-(D-Phe)-Pro-Arg-(2-benzothiazole) (Costanzo et al, 1996) is orally active and has a prolonged half-life of several hours in ViVo (Smith et al, 1996;Bajusz et al, 1996). The second group is characterized by its unique binding to the S3, S1, and S2 subsites of thrombin from the N-terminal residue.…”

mentioning

confidence: 99%

Nonpolar Interactions of Thrombin S‘ Subsites with Its Bivalent Inhibitor: Methyl Scan of the Inhibitor Linker

et al. 1997

View full text Add to dashboard Cite

We have designed bivalent thrombin inhibitors, consisting of a nonsubstrate type active site blocking segment, a hirudin-based fibrinogen recognition exosite blocking segment, and a linker connecting these segments. The inhibition provided by the bivalent inhibitors with various linker lengths revealed that a minimum of 15 atoms was required for simultaneous binding of the two blocking segments of the inhibitor to thrombin without significant distortion. The crystal structure of the inhibitors with a 16-atom linker showed some conformational flexibility in the linker portion which still lies deep in the groove joining the active site and the fibrinogen recognition exosite. Since the thrombin S' subsites are not well characterized, we designed a new strategy to search for possible nonpolar interactions between the linker and the thrombin S' subsites. This strategy, the "methyl scan", is based on the incorporation of a methyl side chain at each atom position of the linker by using sarcosine, D,L-alanine, D,L-3-aminoisobutyric acid, or N-methyl-beta-alanine. The methyl groups on the second and the eighth atom positions of the linker, which correspond to the side chains of the P1' and the P3' residues, respectively, improved the affinity of the inhibitors significantly. Further study of the stereospecificity showed that L-Ala at the P1' residue and D-Ala at the P3' residue preferably improved the affinity of the inhibitors 20- and 25-fold, respectively. Molecular modeling calculations using a methyl probe were also carried out to identify favorable nonpolar interacting sites on the thrombin surface. Two sites were identified in the vicinity of the P1' and the P3' residues, supporting the validity of the methyl scan method. Thus, this study has improved our understanding of the interactions taking place in this groove. In particular, we have been able to show that some specific structural features, such as hydrophobic complementarity between the linker and the thrombin S' subsites, could be exploited and make these inhibitors trivalent.

show abstract

“…Chem. 1995) [ 15 ]. A number of known inhibitors such as inogatran and melagatran (active form of ximelagatran) have been developed based on this motif (Preville Bioorg.…”

Section: Introductionmentioning

confidence: 99%

Influence of Aromatic and Aliphatic Moieties on Thrombin Inhibitors Potency

Poyarkov¹,

Rocabayera²,

Poyarkova³

et al. 2008

Open Biochem J

View full text Add to dashboard Cite

Thrombin is a plasma serine protease that plays a key role in coagulation and hemostasis but also in thromboembolic diseases. Direct thrombin inhibitors could be beneficial for future anticoagulant therapy in the prophylaxis of venous and arterial thrombosis as well as myocardial infarction. To design the efficient thrombin inhibitors we have synthesized and studied peptide-based inhibitors resistant to enzymatic degradation. Compounds with general formula X-DArg-D-Phe-OMe, where X = residue of 3-[6-ethyl-7-hydroxy-3-(4-methyl-thiazol-2-yl)-4-oxo-4H-chromen-2-yl]-propionic acid (chromone) and lauric acid were synthesized by classic methods of peptides synthesis in solution. The comparative inhibitory analysis of prepared compounds in relation to thrombin was conducted. The analysis of the inhibition effect of the peptide with retro-D-sequence modified by residues of natural organic compounds (chromone or fatty acid moiety) has demonstrated that modification with the fatty acid residue appeared to be the most successful one. Introduction of lauric acid residue (Ki = 1,76 μM) maximally increased the inhibition effect. These findings establish an important role of fatty moiety in structure of inhibitors in preferential binding and inhibition of thrombin active side.

show abstract

Active Site-Directed Thrombin Inhibitors: α-Hydroxyacyl-Prolyl-Arginals, New Orally Active Stable Analogues of D-Phe-Pro-Arg-H

Cited by 3 publications

References 2 publications

Synthesis and Evaluation of Diphenyl Phosphonate Esters as Inhibitors of the Trypsin-like Granzymes A and K and Mast Cell Tryptase

Synthesis and Evaluation of Diphenyl Phosphonate Esters as Inhibitors of the Trypsin-like Granzymes A and K and Mast Cell Tryptase

Nonpolar Interactions of Thrombin S‘ Subsites with Its Bivalent Inhibitor: Methyl Scan of the Inhibitor Linker

Influence of Aromatic and Aliphatic Moieties on Thrombin Inhibitors Potency

Contact Info

Product

Resources

About