Biochemical and Biophysical Research Communications
Triglyceride modulation by acifran analogs: activity towards the niacin high and low affinity G protein-coupled receptors HM74A and HM74
Section snippets
Materials and methods
Synthesis of acifran analogs. Acifran analogs were synthesized using standard chemistry techniques, as outlined by the Ayerst Laboratory patents 4,169,202 and 4,244,958. The key step in the synthesis is the base-promoted cyclo-condensation reaction of functionalized α-hydroxyketones with diethyloxalate, to give the furancarboxylic acids. All analogs were purified by recrystallization or flash chromatography and analyzed for purity and integrity using standard analytical techniques (HPLC, LC-MS,
In vivo efficacy of acifran analogs
Selected acifran analogs (compounds 1–5 and 7–9) were examined in the fructose-fed rat model for their ability to lower serum TGs in comparison to acifran that served as a positive control. Table 2 summarizes the results. As expected, acifran exhibited a dose-dependent decrease in serum TGs. Activity is likely due to the S-enantiomer (compound 8), as the R-enantiomer (compound 7) was found to be inactive. Of the other compounds tested only compound 5, which contains a fluorine on the phenyl
Discussion
The synthesis of acifran (AY-25,712; see Table 1 for structure), a known hypolipidemic agent, was first reported by scientists at Ayerst Laboratories in the now expired US Patents 4,169,202 and 4,244,958, and in the literature [22], [23]. It has been suggested that acifran acts to lower serum lipids by a mechanism similar to that of niacin by lowering serum TGs, elevating HDL-C, and possibly lowering LDL-C cholesterol [17]. A compound with such a profile would be of particular value to patients
Acknowledgments
This work was supported, in part, by Small Business Innovation Research grants from the NIDDK to Stuart A. Ross (DK71401) and from NHLBI to Allan R. Moorman (1R43 HL63590-01 and 1R43 HL62831-01). We thank Anne Carrington for development of the fructose-fed rat model and Heather Smiarowski and Kathy Ellwood for animal husbandry.
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Discovery and characterization of GSK256073, a non-flushing hydroxy-carboxylic acid receptor 2 (HCA2) agonist
2015, European Journal of PharmacologyCitation Excerpt :HCA2 (also known as HM74A and GPR109A in human and PUMA-G in mouse) has been identified as a high affinity, Gi-coupled, seven transmembrane receptor for niacin, (Soga et al., 2003; Tunaru et al., 2003; Wise et al., 2003). Acipimox and acifran are also HCA2 agonists and produce qualitatively similar lipid changes and flushing effects to those of niacin (Mahboubi et al., 2006; Soudijn et al., 2007). However other HCA2 agonists devoid of HDLc-raising effects have been described, in spite of their ability to decrease NEFA (Lauring et al., 2012), with some, but not all, producing flushing.
Biological and Pharmacological Roles of HCA Receptors
2011, Advances in PharmacologyCitation Excerpt :However, the most remarkable developments in this area have been published in four recent reviews, to which we refer the interested reader (Boatman et al., 2008; Martres, 2009; Shen, 2009; Shen & Colletti, 2009). Despite the high (> 95%) homology between HCA2 and HCA3 receptors, nicotinic acid is very selective for the HCA2 receptor, whereas acifran is not (see, e.g., Mahboubi et al., 2006; Mandrika et al., 2010; Ren et al., 2009). The most extensive structure–activity study with acifran analogues (Jung et al., 2007) showed that an ethyl rather than a methyl substituent at the chiral center in acifran provided some selectivity for the HCA3 receptor, whereas all other compounds were slightly selective for the HCA2 receptor.
High-Affinity Niacin Receptor GPR109A Agonists
2010, Annual Reports in Medicinal ChemistryCitation Excerpt :Analogs of acifran are typically also dual agonists of GPR109A and GPR109B. Several of these analogs were tested for their ability to decrease TG in a fructose fed rat model, yet none was more efficacious than acifran except analog 7 (racemic), which was equipotent [54]. Analog ent-(+)-8 is 20-fold more potent than racemic acifran and is threefold more potent than niacin in the cAMP whole-cell assay [55].
5-N,N-Disubstituted 5-aminopyrazole-3-carboxylic acids are highly potent agonists of GPR109b
2009, Bioorganic and Medicinal Chemistry LettersPhosphatidylinositol acts through mitogen-activated protein kinase to stimulate hepatic apolipoprotein A-I secretion
2008, Metabolism: Clinical and ExperimentalCitation Excerpt :Niacin (nicotinic acid) is the most effective agent used in the treatment of hypoalphalipoproteinemia and significantly raises HDL cholesterol and apo A-I levels in the blood [20]. Niacin has been shown to impact MAPK through the activation of a G-protein–coupled receptor [21] and activation of PKC [22]. Insulin is also known to stimulate apo A-I secretion through activation of PKC [23], and data from the present study suggest that PI acts similarly.
- 1
These two authors contributed equally to this work.
- 2
Present address: Novartis Institute for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
- 3
Present address: King Pharmaceuticals Research and Development Inc., 4000 CentreGreen Way, Suite 300, Cary, NC 27513, USA.
- 4
Present address: Adipogenix, 801 Albany Street, Boston, MA 02118, USA.