Pyrazole Derivatives as Partial Agonists for the Nicotinic Acid Receptor

• Published in: Journal of medicinal chemistry Vol. 46; no. 18; pp. 3945 - 3951
• Main Authors: van Herk, T, Brussee, J, van den Nieuwendijk, A. M. C. H, van der Klein, P. A. M, IJzerman, A. P, Stannek, C, Burmeister, A, Lorenzen, A
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.08.2003; Amer Chemical Soc
• Subjects: Adipocytes - metabolism; Animals; Biological and medical sciences; Cell Membrane - metabolism; Chemistry, Medicinal; General and cellular metabolism. Vitamins; GTP-Binding Proteins - agonists; In Vitro Techniques; Life Sciences & Biomedicine; Medical sciences; Niacin - pharmacology; Nicotinic Agonists - chemical synthesis; Nicotinic Agonists - chemistry; Nicotinic Agonists - pharmacology; Nicotinic Antagonists - chemical synthesis; Nicotinic Antagonists - chemistry; Nicotinic Antagonists - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Radioligand Assay; Rats; Receptors, Nicotinic - drug effects; Science & Technology; Spleen - metabolism; Structure-Activity Relationship; PROTEIN-COUPLED RECEPTOR; MOLECULAR-IDENTIFICATION; Spleen; Adipocyte; Partial agonist; Five membered ring; Membrane protein; Rat; Nitrogen heterocycle; Rodentia; Nicotinic acid; In vitro; Vertebrata; Mammalia; Structure activity relation; Carboxylic acid; Animal; Affinity; Chemical synthesis; Antilipemic agent; G protein; Biological receptor
• ISSN: 0022-2623; 1520-4804
• 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 [3H]nicotinic acid binding to rat spleen membranes. Potencies and intrinsic activities relative to nicotinic acid were determined by their effects on [35S]GTPγS binding to rat adipocyte and spleen membranes. Interestingly, most compounds were partial agonists. In particular, 2-diazabicyclo[3,3,04,8]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 μM and EC50 values of approximately 6 μM, while their intrinsic activity was only ∼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 μM, an EC50 value of 4.12 μM, 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 μM nicotinic acid and concentration dependently shifted nicotinic acid concentration−response curves to the right, pointing to a competive mechanism of action.