Discovery of 4-(phenyl)thio-1H-pyrazole derivatives as agonists of GPR109A, a high affinity niacin receptor

Abstract

Even though nicotinic acid (niacin) appears to have beneficial effects on human lipid profiles, niacin-induced cutaneous vasodilatation called flushing limits its remedy to patient. GPR109A is activated by niacin and mediates the anti-lipolytic effects. Based on the hypothesis that β-arrestin signaling mediates niacin-induced flushing, but not its anti-lipolytic effect, we tried to find GPR109A agonists which selectively elicit Gi-protein-biased signaling devoid of β-arrestin internalization using a β-lactamase assay. We identified a 4-(phenyl)thio-1H-pyrazole as a novel scaffold for GPR109A agonist in a high throughput screen, which has no carboxylic acid moiety known to be important for binding. While 1-nicotinoyl derivatives (5a-g, 6a-e) induced β-arrestin recruitment, 1-(pyrazin-2-oyl) derivatives were found to play as G-protein-biased agonists without GPR109A receptor internalization. The activity of compound 5a (EC50 = 45 nM) was similar to niacin (EC50 = 52 nM) and MK-6892 (EC50 = 74 nM) on calcium mobilization assay, but its activity at 10 μM on β-arrestin recruitment were around two and five times weaker than niacin and MK-6892, respectively. The development of G-protein biased GPR109A ligands over β-arrestin pathway is attainable and might be important in differentiation of pharmacological efficacy.

Targeting NAD+ in Metabolic Disease: New Insights Into an Old Molecule

“…The long-known lipid-lowering effects of NA may, at least partly, be NAD+ mediated. This hypothesis is favored because the half maximal effective concentration for the GPR109A receptor is in the nanomolar range [ 215 , 216 ]; however, the therapeutic doses of NA are greatly in excess of this amount [ 71 , 217 ]. Moreover, NR ameliorated hypercholesterolemia in mice without activating the GPR109A receptor [ 54 ].…”

Iodine‐Promoted Tandem Pyrazole Annulation and C−H Sulfenylation for the Synthesis of C4‐Sulfenylated Pyrazoles

“…The materials obtained from commercial sources were used without further purification. 1 H NMR, 13 C NMR, and 19 F NMR spectra were recorded on a Brucker Advance III HD 400 MHz spectrometer in CDCl 3 or DMSO-d 6 solution. All chemical shifts were reported in ppm (δ) relative to the internal standard TMS (0 ppm).…”

“…Lee et.al synthesized 3,5‐dimethyl‐4‐(phenylthio)‐1 H ‐pyrazole by a two‐step reaction. Namely, the reaction of 3‐chloro‐2,4‐pentanedione and benzenethiol in the presence of piperidine to form 3‐(phenylthio)pentane‐2,4‐dione, followed by the cyclization with hydrazine hydrate to yield pyrazole thioether derivatives (Scheme 1h) [19] . Based on the above excellent work and our continuous interest, [20] herein we described the domino cyclization and C−H sulfenylation of 1,3‐diarylpropane‐1,3‐dione or 1,3‐diketones with arylsulfonyl hydrazide to build fully substituted pyrazole arylsulfides (Scheme 1i).…”

G protein‐coupled receptors not currently in the spotlight: free fatty acid receptor 2 and GPR35

“…This markedly affects patient compliance in maintaining the treatment. As it was suggested that the flushing effects of niacin treatment might be separable from the lipid‐modifying effects, because the beneficial effects appeared to be G protein‐mediated whilst flushing appeared to be arrestin‐dependent, then efforts to identify and develop G protein‐‘biased’ agonists at this receptor have been made (Shen et al, ; Kim et al, ). However, these have not translated into clinical trials, and currently, although much discussed and studied, no GPCR ligand developed specifically with the concept that signalling ‘bias’ might provide distinct clinical benefits compared to non‐biased ligands at the same receptor has yet received regulatory approval.…”