A family of arginal thrombin inhibitors related to efegatran

Gerald F. Smith, Robert T. Shuman, Trelia J. Craft, Donetta S. Gifford, Kenneth D. Kurz, Noel D. Jones, Nickolay Chirgadze, Robert B. Hermann, William J. Coffman, George Sandusky, Eiry Roberts, Charles Van Jackson

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Three new tripeptide arginal thrombin inhibitors were shown to have potent anticoagulant and antithrombotic activity: D-MePhg-Pro-Arg-H (LY287045), D-1-Tiq-Pro-Arg-H (LY294291), and D-MePhe-Pro-Arg-H (Efegatran). Efegatran and the related arginals differ mechanistically from old and from new anticoagulant agents. As illustrated with x-ray diffraction analysis of crystals of the LY294291 complex with human thrombin, the family of arginals binds thrombin with the P3, P2, and P1 residues interacting with the putative S3, S2, and S1 fibrinogen-binding sites. A hemi-acetal bond at Ser 195 was shown to contribute to the tight-binding reversible competitive thrombin inhibition properties observed with the arginal family. Tight-binding K(ass) values from thrombin inhibition studies correlated with thrombin clotting inhibition potency. The thrombin time (TT) assay was prolonged twofold with 33 nM Efegatran, which demonstrated an apparent K(ass) value of 0.8 x 108 L/mol (for comparison, 17 nM hirudin was required to prolong the TT assay twofold). There are empirical anticoagulant selectivity differences between Efegatran and hirudin, manifested by large activated partial thromboplastin time (aPTT)/TT effect ratios (30 to 55) found with the arginals, as compared to the small aPTT/TT effect ratio (2 to 3) found with hirudin. The underlying anticoagulant mechanism differences between the arginals and hirudin appear to be confined to the aPTT pathway and, therefore, might involve different effects toward thrombin feedback activation of factor VIII. The arginals did not substantially inhibit other coagulation factor serine proteases. Antithrombotic effects of Efegatran and the arginal family occur at low infusion doses in dogs and appear to correlate with effects on TT without requiring perturbation of the aPTT. Selectivity properties regarding the fibrinolytic enzymes were shown to be important for successful use of the arginals in vivo as adjunctive agents during tissue plasminogen activator (t-PA) thrombolysis. The data suggest that LY287045, LY294291, and Efegatran should be expected to be useful as antithrombotic adjuncts to thrombolytic therapy with t-PA, urokinase, or streptokinase and should be expected to spare endogenous fibrinolysis. Efegatran has been evaluated in phase I clinical studies and is currently under clinical investigation in phase II protocols as a new cardiovascular anticoagulant.

Original languageEnglish (US)
Pages (from-to)173-183
Number of pages11
JournalSeminars in Thrombosis and Hemostasis
Volume22
Issue number2
StatePublished - 1996
Externally publishedYes

Fingerprint

efegatran
LY 294291
LY 287045
Thrombin
Thrombin Time
Hirudins
Partial Thromboplastin Time
Anticoagulants
Equidae
Tissue Plasminogen Activator
Acetals
Streptokinase
Competitive Binding
Blood Coagulation Factors
Thrombolytic Therapy
Urokinase-Type Plasminogen Activator
Factor VIII
Serine Proteases
Fibrinolysis
Fibrinogen

Keywords

  • Antithrombin
  • Arginal
  • Efegatran
  • Thrombin
  • Thrombin inhibition

ASJC Scopus subject areas

  • Hematology

Cite this

Smith, G. F., Shuman, R. T., Craft, T. J., Gifford, D. S., Kurz, K. D., Jones, N. D., ... Van Jackson, C. (1996). A family of arginal thrombin inhibitors related to efegatran. Seminars in Thrombosis and Hemostasis, 22(2), 173-183.

A family of arginal thrombin inhibitors related to efegatran. / Smith, Gerald F.; Shuman, Robert T.; Craft, Trelia J.; Gifford, Donetta S.; Kurz, Kenneth D.; Jones, Noel D.; Chirgadze, Nickolay; Hermann, Robert B.; Coffman, William J.; Sandusky, George; Roberts, Eiry; Van Jackson, Charles.

In: Seminars in Thrombosis and Hemostasis, Vol. 22, No. 2, 1996, p. 173-183.

Research output: Contribution to journalArticle

Smith, GF, Shuman, RT, Craft, TJ, Gifford, DS, Kurz, KD, Jones, ND, Chirgadze, N, Hermann, RB, Coffman, WJ, Sandusky, G, Roberts, E & Van Jackson, C 1996, 'A family of arginal thrombin inhibitors related to efegatran', Seminars in Thrombosis and Hemostasis, vol. 22, no. 2, pp. 173-183.
Smith GF, Shuman RT, Craft TJ, Gifford DS, Kurz KD, Jones ND et al. A family of arginal thrombin inhibitors related to efegatran. Seminars in Thrombosis and Hemostasis. 1996;22(2):173-183.
Smith, Gerald F. ; Shuman, Robert T. ; Craft, Trelia J. ; Gifford, Donetta S. ; Kurz, Kenneth D. ; Jones, Noel D. ; Chirgadze, Nickolay ; Hermann, Robert B. ; Coffman, William J. ; Sandusky, George ; Roberts, Eiry ; Van Jackson, Charles. / A family of arginal thrombin inhibitors related to efegatran. In: Seminars in Thrombosis and Hemostasis. 1996 ; Vol. 22, No. 2. pp. 173-183.
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