4-Phenyl-4H-pyrans as IKCa channel blockers

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Abstract

4-Phenyl-4H-pyrans have been identified as potent and specific IKCa channel blockers. Their synthesis and structure–activity relationships are described. A selected derivative, rac-11, reduces the infarct volume in a rat subdural hematoma model of traumatic brain injury after iv administration.

Abstract

4-Phenyl-4H-pyrans have been identified as potent and specific IKCa channel blockers. Their synthesis and structure–activity relationships are described. A selected derivative, rac-11, reduces the infarct volume in a rat subdural hematoma model of traumatic brain injury after iv administration.

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Chemistry

The pyrans have been synthesised based on the method of Wolinsky following reaction Scheme 2.9 Zn(OAc)2-mediated condensation of 1,3-dicarbonyl compounds with aromatic aldehydes delivered 4-phenyl-pyrans in high yields. Compound rac-7 and rac-11 were first obtained as side products (10%) of the syntheses of 5 and 10, respectively, possibly due to the strong acetylating reaction conditions. However, rac-7 or rac-11 can also be obtained in a directed synthesis.10, 11

Biology

IKCa channel inhibition was determined measuring ionomycin-induced Rb+ efflux of pre-loaded rat C6BU1 glioma cells. IKCa channel expression as well as L-type Ca2+ channel absence was ensured via PCR on the m-RNA level using gene-specific primers. Charybdotoxin was used as an internal standard (IC50=9 nM).12

Activity on other ion channels was measured on the basis of affinities to known binding sites.13 Blood pressure and heart rate measurements in rats were performed as described. 14

Results

The encouraging submicromolar activity of the simple dimethyl ester 2 (IC50=160 nM) clearly indicated that isoelectronic replacement of Nifedipine's (1) NH group is a suitable strategy to separate Ca2+ channel and IKCa channel antagonist SAR. The activity of 2 could be further enhanced by one order of magnitude on introducing an electron-withdrawing substituent such as Cl into the 4-position of the phenyl ring leading to 3. Whereas the 3-Cl derivative (4) exhibited comparable activity, the 2-Cl

Acknowledgments

We would like to thank L. Telan for careful reading of the manuscript and S. Goldmann for helpful discussions.

References (16)

  • N.J. Logsdon et al.

    J. Biol. Chem.

    (1997)
    W.J. Joiner et al.

    Proc. Natl. Acad. Sci., U.S.A.

    (1997)
  • J.D. Miller et al.

    Neurosurg.

    (1990)
  • G. Gardos

    Biochim. Biophys. Acta

    (1958)
  • A. Schwab et al.

    Physiol. Renal Physiol.

    (2001)
    A. Schwab

    Curr. Res. Ion Channel Mod.

    (1998)
  • R. Khanna et al.

    Am. J. Physiol. Cell. Physiol.

    (2001)
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