title: Thrombin inhibitors based on ketone derivatives of arginine and lysine.
abstract: Much attention is currently focused on inhibitors of thrombin as potential anticoagulants. We have previously reported thrombin inhibitors based on fragments of fibrinogen containing a ketomethylene isostere at P1-P'1. We now expand on these early findings by reporting on tripeptide based inhibitors of thrombin containing arginine or lysine ketones at the C-terminus. A large variety of such ketones have been studied and compared in their ability to increase the thrombin time in human plasma. In the case of arginine or lysine ketones the order of activity (i.e. decreasing IC50 TT) was: alkyl ketones < beta-ketoesters < difluoro beta-ketoamides < alkyloxymethyl ketones < fluoroketones. Lysine analogues were generally found to be ca. ten-fold less active than their arginine counterparts. However, in the case of alpha-ketoesters the lysine derivatives were superior to all the types of arginine ketones studied (including the arginine alpha-keto ester derived thrombin inhibitor). A mechanistic explanation of the relative inactivity of the arginine alpha-keto ester derivative is proposed. All the highly electrophilic ketones were found to be slow-binding with thrombin.
authors.affiliation: Ferring Research Institute, Southampton University Research Centre, Chilworth, UK.
authors.forename: D M
authors.initials: DM
authors.lastname: Jones
authors.forename: B
authors.initials: B
authors.lastname: Atrash
authors.forename: H
authors.initials: H
authors.lastname: Ryder
authors.forename: A C
authors.initials: AC
authors.lastname: Teger-Nilsson
authors.forename: E
authors.initials: E
authors.lastname: Gyzander
authors.forename: M
authors.initials: M
authors.lastname: Szelke
mesh_terms: D000595:Amino Acid Sequence; D000925:Anticoagulants / Q000138:chemical synthesis / Q000494:pharmacology*; D000991:Antithrombins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives* / Q000737:chemistry; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008239:Lysine / Q000031:analogs & derivatives* / Q000737:chemistry; D013058:Mass Spectrometry; D008956:Models, Chemical; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013918:Thrombin Time
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D004952:Esters; D007659:Ketones; D009842:Oligopeptides; D001120:Arginine; D013917:Thrombin; D008239:Lysine