Potent effects of novel anti-platelet aggregatory cilostamide analogues on recombinant cyclic nucleotide phosphodiesterase isozyme activity.

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  • Additional Information
    • Source:
      Publisher: Elsevier Science Country of Publication: England NLM ID: 0101032 Publication Model: Print Cited Medium: Print ISSN: 0006-2952 (Print) Linking ISSN: 00062952 NLM ISO Abbreviation: Biochem Pharmacol Subsets: MEDLINE
    • Publication Information:
      Publication: Oxford : Elsevier Science
      Original Publication: Oxford, New York [etc.] Paragamon Press.
    • Subject Terms:
      3',5'-Cyclic-AMP Phosphodiesterases/*antagonists & inhibitors ; Isoenzymes/*antagonists & inhibitors ; Platelet Aggregation/*drug effects ; Platelet Aggregation Inhibitors/*pharmacology ; Quinolones/*pharmacology; 3',5'-Cyclic-AMP Phosphodiesterases/metabolism ; Blood Platelets/drug effects ; Blood Platelets/metabolism ; Cells, Cultured ; Cyclic AMP/metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 1 ; Cyclic Nucleotide Phosphodiesterases, Type 3 ; Humans ; Isoenzymes/metabolism ; Quinolines/pharmacology ; Recombinant Proteins/antagonists & inhibitors ; Semicarbazides/pharmacology ; Urea/analogs & derivatives ; Urea/pharmacology
    • Abstract:
      The inhibitory potential of novel anti-platelet aggregatory cilostamide analogues on phosphodiesterase (PDE) isozyme activities was investigated with recombinant PDE isozymes expressed in a baculovirus/ Sf9 expression system. The recombinant enzymes (PDE1-PDE5 and PDE7) showed Km values and sensitivities to selective inhibitors similar to those reported previously for native enzymes purified from tissues. The cyclooctylurea derivative OPC-33540 (6-[3-[3-cyclooctyl-3-[(1R*,2R*)-2-hydroxycyclohexyl]ureido]-propoxy]-2(1H)-quinolinone) inhibited recombinant PDE3A (IC50 = 0.32 nM) more potently and selectively than the classical PDE3 inhibitors cilostamide, cilostazol, milrinone, and amrinone. The cyclopropylurea derivative OPC-33509 [(-)-6-[3-[3-cyclopropyl-3-[(1R,2R)-2-hydroxycyclohexyl]ureido]-propoxy]-2(1H)-quinolinone] was less potent (IC50 = 0.10 microM) than OPC-33540, demonstrating that the cyclooctyl moiety was important for a potent inhibitory effect. In platelets, OPC-33540 potentiated cyclic AMP accumulation concentration-dependently in both the absence and the presence of 3 nM prostaglandin E1 (PGE1) (doubling concentrations: 32.5 and 6.2 nM, respectively). OPC-33540 inhibited thrombin-induced platelet aggregation potently (Ic50 = 27.8 nM). The anti-platelet aggregation effect also was stimulated in the presence of 3 nM PGE1 (IC50 = 6.0 nM). There was a good correlation between the IC50 values of PDE3 inhibitors in this study for recombinant PDE3A activity and their IC50 values for thrombin-induced platelet aggregation (r = 0.998). These data demonstrated that OPC-33540 is a highly selective and potent PDE3 inhibitor and a useful probe for identification of the intracellular functions of PDE3.
    • Accession Number:
      0 (Isoenzymes)
      0 (OPC 33536)
      0 (OPC 33540)
      0 (Platelet Aggregation Inhibitors)
      0 (Quinolines)
      0 (Quinolones)
      0 (Recombinant Proteins)
      0 (Semicarbazides)
      45S5605Q18 (cilostamide)
      8W8T17847W (Urea)
      E0399OZS9N (Cyclic AMP)
      EC 3.1.4.17 (3',5'-Cyclic-AMP Phosphodiesterases)
      EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 1)
      EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 3)
      EC 3.1.4.17 (PDE3A protein, human)
      J9J6NK6W4U (OPC 33509)
    • Publication Date:
      Date Created: 20000122 Date Completed: 20000203 Latest Revision: 20190623
    • Publication Date:
      20221213
    • Accession Number:
      10.1016/s0006-2952(99)00346-9
    • Accession Number:
      10644042