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Chemical Compound Review:

Fprmecl (2S)-N-[(1S)-1-[[(3S)-1- chloro-6...

Synonyms: FPRCK, Phe-pro-arg-CK, AC1L3GOH, LS-176430, C21H29ClN6O5, ...

Lumsden, A.B. et al., Qiu, X. et al., Vijayalakshmi, J. et al., Glembotski, C.C. et al., Francischetti, I.M. et al., et al.

Bang, Fielder,

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Disease relevance of Fprmecl

To evaluate the relative antithrombotic efficacy and hemostatic safety of antithrombin therapy for vascular thrombus formation at sites of mechanical vascular injury, we administered the potent and specific irreversible synthetic antithrombin D-PHE-PRO-ARG chloromethyl ketone (D-FPRCH2Cl) after performing carotid endarterectomies in baboons [1].
After 48 h, alpha Th induced hypertrophy, sarcomeric organization, and enhanced atrial natriuretic factor (ANF) expression, all of which were blocked by the alpha Th-selective protease inhibitor, D-Phe-Pro-Arg-chloromethyl ketone [2].

High impact information on Fprmecl

D-Phe-Pro-Arg-chloromethyl ketone (PPACK) active site blocked thrombin and the catalytically inactive thrombin mutant S205A did not affect u-PAR mRNA levels [3].
To characterize the initial adsorption of thrombin to the endothelium in vivo, an enzymatically inactive derivative, FPR-thrombin (i.e., thrombin inactivated by D-Phe-Pro-Arg-chloromethyl ketone), was prepared [4].
Phosphorylation of EF-2 was not increased by treatment with D-Phe-Pro-Arg-chloromethyl ketone thrombin, phorbol dibutyrate, forskolin, or 8-bromo-cGMP [5].
In addition, anophelin-gamma-thrombin complex formation is prevented by treatment of the enzyme with D-Phe-Pro-Arg-chloromethyl ketone (PPACK), a reagent that irreversibly blocks the catalytic site of thrombin [6].
Both urokinase and tissue-type PA had the ability to proteolyze IGFBP-3 and were, in contrast to the >150-kDa protease activity, inhibited by the specific PA inhibitor D-PHE-PRO-ARG chloromethyl ketone [7].

Biological context of Fprmecl

With the determination of isomorphous structures of hirugen-thrombin and D-Phe-Pro-Arg chloromethyl ketone (PPACK)-thrombin, the changes that occur in the active site that affect the kinetics of chromogenic substrate hydrolysis on binding to the fibrinogen recognition exosite have been determined [8].

Anatomical context of Fprmecl

Furthermore, adding tPA that had been previously treated with the protease inhibitor, D-Phe-Pro-Arg-chloromethyl ketone HCl (PPACK), also decreased neutrophil O2.- generation in vitro (P < 0.05) [9].

Associations of Fprmecl with other chemical compounds

The interactions of D-Phe1'-Pro2'-beta-homoArg3' with the active site of thrombin were essentially identical to those of related structures of PPACK- (D-Phe-Pro-Arg chloromethyl ketone) and hirulog 1-thrombin, with the guanidinium function of the arginyl P1 residue forming a hydrogen-bonding ion pair with Asp189 of the S1 site [10].
The cleavage of aFGF by thrombin is inhibited by heparin (50 micrograms/mL) and is completely blocked by the irreversible thrombin inhibitors D-Phe-Pro-Arg chloromethyl ketone and hirudin [11].
Immobilized leupeptin, L-lysine, or D-Phe-Pro-Arg-chloromethyl ketone can also direct outgrowth towards their immobilized areas, as do zones of laminin or fibronectin [12].

References

Lasting safe interruption of endarterectomy thrombosis by transiently infused antithrombin peptide D-Phe-Pro-ArgCH2Cl in baboons. Lumsden, A.B., Kelly, A.B., Schneider, P.A., Krupski, W.C., Dodson, T., Hanson, S.R., Harker, L.A. Blood (1993) [Pubmed]
Myocardial alpha-thrombin receptor activation induces hypertrophy and increases atrial natriuretic factor gene expression. Glembotski, C.C., Irons, C.E., Krown, K.A., Murray, S.F., Sprenkle, A.B., Sei, C.A. J. Biol. Chem. (1993) [Pubmed]
Effect of thrombin, the thrombin receptor activation peptide, and other mitogens on vascular smooth muscle cell urokinase receptor mRNA levels. Reuning, U., Little, S.P., Dixon, E.P., Bang, N.U. Blood (1994) [Pubmed]
Comparative behavior of thrombin and an inactive derivative, FPR-thrombin, toward the rabbit vascular endothelium. Heparin liberates FPR-thrombin from the endothelium in vivo. Hatton, M.W., Moar, S.L. Circ. Res. (1990) [Pubmed]
Thrombin and histamine stimulate the phosphorylation of elongation factor 2 in human umbilical vein endothelial cells. Mackie, K.P., Nairn, A.C., Hampel, G., Lam, G., Jaffe, E.A. J. Biol. Chem. (1989) [Pubmed]
Anophelin: kinetics and mechanism of thrombin inhibition. Francischetti, I.M., Valenzuela, J.G., Ribeiro, J.M. Biochemistry (1999) [Pubmed]
Human pregnancy serum contains at least two distinct proteolytic activities with the ability to degrade insulin-like growth factor binding protein-3. Bang, P., Fielder, P.J. Endocrinology (1997) [Pubmed]
The isomorphous structures of prethrombin2, hirugen-, and PPACK-thrombin: changes accompanying activation and exosite binding to thrombin. Vijayalakshmi, J., Padmanabhan, K.P., Mann, K.G., Tulinsky, A. Protein Sci. (1994) [Pubmed]
Tissue plasminogen activator (tPA) inhibits human neutrophil superoxide anion production in vitro. Stringer, K.A., Lindenfeld, J., Repine, A.J., Cohen, Z., Repine, J.E. Inflammation (1997) [Pubmed]
Structure of the hirulog 3-thrombin complex and nature of the S' subsites of substrates and inhibitors. Qiu, X., Padmanabhan, K.P., Carperos, V.E., Tulinsky, A., Kline, T., Maraganore, J.M., Fenton, J.W. Biochemistry (1992) [Pubmed]
Thrombin inactivates acidic fibroblast growth factor but not basic fibroblast growth factor. Lobb, R.R. Biochemistry (1988) [Pubmed]
Protease inhibitors influence the direction of neurite outgrowth. Hawkins, R.L., Seeds, N.W. Brain Res. Dev. Brain Res. (1989) [Pubmed]

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