Pyrazole Derivatives as Partial Agonists for the Nicotinic Acid Receptor

Abstract

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.

Niacin, an old drug with a new twist

“…Several pharmaceutical companies began developing selective agonists of GPR109A (42)(43)(44)(45)(46)(47). Walters et al ( 48 ) suggested that the effects of niacin on FFAs and fl ushing could be segregated.…”

A review of recent progress (2002-2012) on the biological activities of pyrazoles

“…A series of pyrazole-3-carboxylic acids has been reported as partial agonists for the nicotinic acid receptor 117 aimed to treat atherosclerosis. It was postulated that partial agonism might result in tissue selectivity.…”

“…119 Other pyrazoles with anti-lipidemic activity are compounds 117 and 118. 117 It has been postulated that compared to full agonists, partial agonists may exhibit reduced adverse effects. Interestingly, compound 117, a partial agonist in the GTPgS (guanosine 5'-O-[-thio]triphosphate) assay, turned out to be a full agonist in the cAMP whole-cell assay.…”

Interseção cardiorrenal: confluência para o futuro

“…Preliminary studies demonstrate that Lp(a) levels may be reduced with niceritrol (a niacin prodrug), plasma apheresis and renal transplantation 30 . In addition, pyrazole derivatives as partial agonists for the nicotinic acid receptor may be future therapeutic targets for decreasing Lp(a) levels 31 .…”