Pyrazole derivatives as partial agonists for the nicotinic acid receptor

J Med Chem. 2003 Aug 28;46(18):3945-51. doi: 10.1021/jm030888c.


Nicotinic acid as a hypolipidemic agent appears unique due to its potential to increase HDL cholesterol levels to a greater extent than other drugs. However, it has some side effects, among which severe skin flushing is the most frequent and often limits patients' compliance. In a search for novel agonists for the recently identified and cloned G protein-coupled nicotinic acid receptor, we synthesized a series of substituted pyrazole-3-carboxylic acids that proved to have substantial affinity for this receptor. The affinities were measured by inhibition of [(3)H]nicotinic acid binding to rat spleen membranes. Potencies and intrinsic activities relative to nicotinic acid were determined by their effects on [(35)S]GTPgammaS binding to rat adipocyte and spleen membranes. Interestingly, most compounds were partial agonists. In particular, 2-diazabicyclo[3,3,0(4,8)]octa-3,8-diene-3-carboxylic acid (4c) and 5-propylpyrazole-3-carboxylic acid (4f) proved active with K(i) values of approximately 0.15 microM and EC(50) values of approximately 6 microM, while their intrinsic activity was only approximately 50% when compared to nicotinic acid. Even slightly more active was 5-butylpyrazole-3-carboxylic acid (4g) with a K(i) value of 0.072 microM, an EC(50) value of 4.12 microM, and a relative intrinsic activity of 75%. Of the aralkyl derivatives, 4q (5-(3-chlorobenzyl)pyrazole-3-carboxylic acid) was the most active with a relatively low intrinsic activity of 39%. Partial agonism of the pyrazole derivatives was confirmed by inhibition of G protein activation in response to nicotinic acid by these compounds. The pyrazoles both inhibited the maximum effect elicited by 100 microM nicotinic acid and concentration dependently shifted nicotinic acid concentration-response curves to the right, pointing to a competitive mechanism of action.

MeSH terms

  • Adipocytes / metabolism
  • Animals
  • Cell Membrane / metabolism
  • GTP-Binding Proteins / agonists
  • In Vitro Techniques
  • Niacin / pharmacology
  • Nicotinic Agonists / chemical synthesis*
  • Nicotinic Agonists / chemistry
  • Nicotinic Agonists / pharmacology
  • Nicotinic Antagonists / chemical synthesis
  • Nicotinic Antagonists / chemistry
  • Nicotinic Antagonists / pharmacology
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Radioligand Assay
  • Rats
  • Receptors, Nicotinic / drug effects*
  • Spleen / metabolism
  • Structure-Activity Relationship


  • Nicotinic Agonists
  • Nicotinic Antagonists
  • Pyrazoles
  • Receptors, Nicotinic
  • Niacin
  • GTP-Binding Proteins