Enhanced protein C activation and inhibition of fibrinogen cleavage by a thrombin modulator.
A modulator of the enzymatic activity of human thrombin, designated LY254603, was identified that enhances the thrombin-catalyzed generation of the anticoagulant factor activated protein C, yet inhibits thrombin-dependent fibrinogen clotting. By means of mutant substrates, it was shown that LY254603 mediates the change in enzymatic substrate specificity through an alteration in thrombin's S3 substrate recognition site, a mechanism that appeared to be independent of allosteric changes induced by either sodium ions or by thrombomodulin. This compound may represent the prototype of a class of agents that specifically modulates the balance between thrombin's procoagulant and anticoagulant functions.
Berg
D T
DT
Cardiovascular Research Division, Lilly Research Laboratories, Indianapolis, IN 46285-0444, USA.
Wiley
M R
MR
Grinnell
B W
BW
D001777:Blood Coagulation / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology; D002794:Choline / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005340:Fibrinogen / Q000378:metabolism*; D006801:Humans; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology*; D010314:Partial Thromboplastin Time; D010647:Phenyl Ethers / Q000737:chemistry / Q000494:pharmacology*; D011486:Protein C / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000378:metabolism; D012965:Sodium Chloride / Q000494:pharmacology; D013379:Substrate Specificity / Q000187:drug effects; D013917:Thrombin / Q000494:pharmacology*; D018180:Thrombomodulin / Q000378:metabolism
C101086:LY 254603; D009281:Naphthalenes; D010647:Phenyl Ethers; D011486:Protein C; D011994:Recombinant Proteins; D018180:Thrombomodulin; D012965:Sodium Chloride; D005340:Fibrinogen; D013917:Thrombin; D002794:Choline; D002118:Calcium