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New bivalent thrombin inhibitors with N(alpha)(methyl)arginine at the P1-position. 2000

T Steinmetzer, and M Batdordshjin, and F Pineda, and L Seyfarth, and A Vogel, and S Reissmann, and J Hauptmann, and J Stürzebecher
Institut für Biochemie und Biophysik, Friedrich-Schiller-Universität, Jena, Germany.

A series of bivalent thrombin inhibitors was synthesized, consisting of a d-phenylalanyl-prolyl-N(alpha)(methyl)arginyl active site blocking segment, a fibrinogen recognition exosite inhibitor part, and a peptidic linker connecting these fragments. The methylation of the P1 amino acid led to a moderate decrease in affinity compared with the unmethylated analog. In addition, it prevented the thrombin catalyzed proteolysis, independent of the P1' amino acid used. This is a significant advantage compared to the original hirulogs, which strictly require a proline as P1' amino acid to reduce the cleavage C-terminal to the arginyl residue. Several analogs were prepared by incorporation of different P1' amino acids found in natural thrombin substrates. The most potent inhibitor was I-11 [dCha-Pro-N(Me)Arg-Thr-(Gly)5-DYEPIPEEA-Cha-dGlu] with a Ki of 37 pM. I-11 is highly selective and no inhibition of the related serine proteases trypsin, factor Xa and plasmin was observed. The stability of I-11 in human plasma in vitro was strongly improved compared to hirulog-1. In addition, a significantly reduced plasma clearance of I-11 was observed after intravenous injection in rats. Results from molecular modeling suggest that a strong reorganization of the hydrogen bonds in the active site of thrombin may result in the proteolytic stability found in this inhibitor series.

UI MeSH Term Description Entries
D008969 Molecular Sequence Data Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories. Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000595 Amino Acid Sequence The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION. Protein Structure, Primary,Amino Acid Sequences,Sequence, Amino Acid,Sequences, Amino Acid,Primary Protein Structure,Primary Protein Structures,Protein Structures, Primary,Structure, Primary Protein,Structures, Primary Protein
D000991 Antithrombins Endogenous factors and drugs that directly inhibit the action of THROMBIN, usually by blocking its enzymatic activity. They are distinguished from INDIRECT THROMBIN INHIBITORS, such as HEPARIN, which act by enhancing the inhibitory effects of antithrombins. Antithrombin,Direct Antithrombin,Direct Antithrombins,Direct Thrombin Inhibitor,Direct Thrombin Inhibitors,Antithrombin, Direct,Antithrombins, Direct,Inhibitor, Direct Thrombin,Thrombin Inhibitor, Direct,Thrombin Inhibitors, Direct
D019323 omega-N-Methylarginine A competitive inhibitor of nitric oxide synthetase. D-NMMA,L-Monomethylarginine,L-NMMA,NG-Monomethyl-L-Arginine,L-NG-Monomethyl Arginine,N(G)-Methylarginine,N(G)-Monomethyl-D-Arginine,N(G)-Monomethylarginine,N(omega)-Monomethyl-L-Arginine,Arginine, L-NG-Monomethyl,L Monomethylarginine,L NG Monomethyl Arginine,NG Monomethyl L Arginine,omega N Methylarginine

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