Discovery of pyrazolopyrimidines as the first class of allosteric agonists for the high affinity nicotinic acid receptor GPR109A

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Abstract

Pyrazolopyrimidines were discovered as the first class of allosteric agonists for the high affinity nicotinic acid receptor GPR109A. In addition to its intrinsic activity, compound 9n significantly enhances nicotinic acid binding to the receptor, thereby potentiating the functional efficacy of nicotinic acid.

Graphical abstract

Pyrazolopyrimidines were discovered as the first class of allosteric agonists for the high affinity nicotinic acid receptor GPR109A. In addition to its intrinsic activity, compound 9n significantly enhances nicotinic acid binding to the receptor, thereby potentiating the functional efficacy of nicotinic acid.

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References and notes (19)

  • R.H. Knopp

    N. Engl. J. Med.

    (1999)
  • M.J. Marino et al.

    Curr. Opin. Pharmacol.

    (2006)
    Z.-G. Gao et al.

    Drug Discov. Today: Disea. Mech.

    (2006)
  • (a)Boatman, D. P.; Schrader, T. O.; Semple, G.; Skinner, P. J.; Jung, J.-K. Patent WO 2006/069242...(b)Semple, G.; Schrader, T.; Skinner, P. J.; Colletti, S. L.; Gharbaoui, T.; Imbriglio, J. E.; Jung, J.-K.; Liang, R.;...P.J. Skinner et al.

    Bioorg. Med. Chem. Lett.

    (2007)
  • Cao, G.; Xue, C.-B.; Anand, R.; Huang, T.; Kong, L.; Glenn, J.; Feng, H. Patent WO 2007/015744...
  • A.K.P. Taggart et al.

    J. Biol. Chem.

    (2005)
  • F. Bruni et al.

    J. Heterocycl. Chem.

    (1995)
  • W.J. Mack et al.

    Stroke

    (1993)
    E.A. Nikkila et al.

    Br. Med. J.

    (1984)
  • P.L. Canner et al.

    J. Am. Coll. Cardiol.

    (1986)
    L.B. Pritzker

    Crit. Rev. Clin. Lab. Sci.

    (1998)
    A.J. Taylor et al.

    Circulation

    (2004)
  • A. Schaub et al.

    Eur. J. Immunol.

    (2001)
There are more references available in the full text version of this article.

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