Niacin analogs

Prior to the discovery of niacin receptors, medicinal chemistry efforts were mainly directed toward small heterocyclic carboxylic acids that are structurally similar to niacin. Systematic study of nitrogen-containing five- and six-membered heterocyclic carboxylic acids revealed that activity at GPR109A was significantly reduced for any of the variants of niacin shown in general structures (A and B) [45,46]. These heterocycles include pyrazole, isoxazole, thiazole, pyrazine, and pyrimidine. 

Acipimox (5) was introduced in Europe to treat hyperlipidemia in 1985 [47,48]. Acipimox is a weak agonist of GPR109A with micromolar binding and functional activity. Like niacin, acipimox raises HDL-C and triggers vasodilation in humans. However, it remains unclear whether acipimox causes mild hyperglycemia as is observed with niacin [49,50]. 

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Niacin Analogs That Induce Differentiation of Friend Erythroleukemia Cells are Able to Cause DNA Hypomethylation... 

Niacin analogs were compared at 10 mM for ejects on induction of differentiation, Hb accumulation, poly(ADP-ribose) synthetase in vitro, and on DNA methylase activity in cell-free assays and in growing cells (Table 1). None of these compounds were active as inhibitors of DNA methylase activity in cell-free assays. In contrast, these compounds were found to have differential effects on poly(ADP-ribose) synthetase activity in isolated nuclei, as measured by a modified procedure of Hayaishi (23). Inhibition of poly(ADP-ribose) synthetase by these compounds did not, as previously hypothesized, correlate with their ability to induce Hb synthesis and differentiation. N -MNA and 6-MNA were not able to inhibit poly(ADP-ribose) synthetase activity in isolated nuclei when present at 5 mM, whereas NAm and 5-MNA both possess inhibitory activity in vitro. When these compounds were incubated at 10 mM in cell culture for 24 hr, all those able to induce differentiation were also able to cause DNA hypomethylation, as judged by their effect on methyl-accepting abilities of DNA isolated from these cells. 

Table 1. Comparison of the effects of niacin analogs on nuclear events relating to the induction of differentiation of FELCs. Compounds were present at 10 mM in all assays, except ADP-ribose transferase activity, where they were 5 mM. All data represent the mean of triplicate assays with standard error, except % ADP-ribose transferase activity, where only the mean was included.

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]. The selectivity was also improved with respect to acifran with 10-fold selectivity for GPR109A over GPR109B. The importance of the absolute configuration of ent-(+)-8, which is tentatively assigned S, is demonstrated by the 70-fold better cAMP whole-cell activity of the eutomer compared to that of the distomer. 

Nicotinamide adenine dinucleotide (NAD+ in its oxidized form) and its close analog nicotinamide adenine dinucleotide phosphate (NADP+) are composed of two nucleotides joined through their phosphate groups by a phosphoanhydride bond (Fig. 13-15a). Because the nicotinamide ring resembles pyridine, these compounds are sometimes called pyridine nucleotides. The vitamin niacin is the source of the nicotinamide moiety in nicotinamide nucleotides. 

The niacin vitamers in foods include nicotinic acid and nicotinamide (Fig. 4), which occur in limited quantities in the free form, and their coenzymes, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) (93,96). The nicotinic acid analog of NAD as well as nicotinamide and nicotinic acid mononucleotides also occur in nature. In addition, niacin occurs as nicotinyl esters bound to polysaccharides, peptides, and glycopep-tides, which are known as niacytin and niacynogens, respectively. In general, the niacin vitamers in cereal grains and other seeds are principally the nicotinic acid forms, whereas those in meat and fish are primarily the nicotinamide forms (94,95). 

There are several analogs and antimetabolites of niacin that are of potential use or metabolic interest. The closely related isoniazid is commonly used for treatment of tuberculosis indeed, nicotinamide itself has been used for that purpose. Nicotinic acid diethylamide ( nikethamide ) is used as a... 

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