Nicotinamide N-oxides

Researchers at Celltech identified a novel series of nicotinamide N-oxides as CXCR2 antagonist [127]. For instance, 6 hloro derivatives 40 was shown to inhibit CXCR2 

In a more recent publication, Dompe discussed their efforts to identify follow-up compounds that produce more favorable PK characteristics than reparixin [132]. One such compound is trifluoromethanesulfonate 44, which inhibited both CXCL8- and CXCLl-induced PMN chemotaxis with equal potencies (IC50 8.4 and 26 nM, respectively) [133] and in addition gave excellent rat PK properties Cl 4.1 mlmin kg , P 72%) [134]. Extensive in vivo profiling showed 44 to be orally efficacious in a range of inflammatory disease models such as the rat adjuvant-induced arthritis model. 

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FIGURE I A reconstructed extracted ion chromatogram of nicotinic acid and its six metabolites under HILIC conditions. Column Hypersil silica (4.6 X 50 mm) at a flow rate of 4 mL/min. Mobile phase A is water, mobile phase B is acetonitrile, both containing 1% formic acid. Gradient is 0.01-0.25 min 90% B to 65% B 0.25-0.90 min 65% B to 50% B. NA nicotinic acid NAM nicotinamide NUA nicotinuric acid 2-PY l-methyl-2-pyridone-5-carboxamide l-MNAM I-methyl-nicotinamide NAMO nicotinamide-N-oxide 4-PY l-methyl-4-pyridone-5-carboxamide. (Reprinted with permission from Reference 20.)... 

Figure 8.3. Metabolites of nicotinamide and nicotinic acid. Nicotinamide deamidase (nicotinamidase), EC 3.5.1.19 nicotinamide N-methyltransferase, EC 2.1.1.1 aldehyde dehydrogenase, EC 1.1.1.1. Relative molecular masses (Mr) nicotinamide, 123.1 nicotinic acid, 122.1 nicotinamide N-oxide, 139.1 iV -methyl nicotinamide, 139.1 trigonelline, 137.1 nicotinuiic acid, 179.2 and methyl pyridone carboxamides, 154.1.

Murray, K. N., Watson, J. G., and Chaykin, S., 1966, Catalysis of the direct transfer of oxygen from nicotinamide N-oxide to xanthine by xanthine oxidase, J. Biol. Chem. 241 4798n4801. 

Nicotinamide-N-oxide (71) is converted by a mixture of phosphorus pentachloride and phosphorus oxychloride in 52% yield to 2-chloronicoti-nonitrile (72) (54JOCI633), whereas 2-phenylpyridine-N-oxide (73) reacts with sulfuryl chloride to afford a mixture of 43% of 2-phenyl-4-chloropyridine (74) and 35% of 2-phenyl-6-chloropyridine (75) (53CJC457). 

Kitamura, S., and Tatsumi, K. Involvement of liver aldehyde oxidase in the reduction of nicotinamide N-oxide. Biochem Biophys Res Commun 120 692-703, 19846. 

Nicotinamide was also partly extracted in this process and eluted at about 10 min (Fig. 16B). Nicotinamide N-oxide eluted at the same time even when sodium 1-octanesulfonate was omitted from the mobile phase, although identification of the peak of nicotinamide N-oxide was easier in the presence of sodium 1-octanesulfonate than in its absence, because no interfering peaks were eluted at the elution time of nicotinamide N-oxide. Daily urinary excretion of nicotinamide IV-oxide in rats, mice, guinea pigs, and hamsters is given in Table 5. 

K Shibata. High-performanee liquid chromatographic measurement of nicotinamide N-oxide in urine after extracting with chloroform. Agric Biol Chem 53 1329-1331, 1989. 

Other urinary excretion products of niacin include nicotinuric acid (nicotinoyl glycine) nicotinamide N-oxide, and trigonelline (N -methyl nicotinic acid) the latter may arise from bacterial action in the gut or from the absorption of this substance from foods. The pattern of the different turnover metabolites varies between species, between diets (depending partly on the ratio of nicotinamide to nicotinic acid in the diet), and partly with niacin status thus there are complex regulatory mechanisms to be considered. 

By immunizing animals with specific hapten-carrier conjugates, we have been very successful in obtaining specific antibodies to nicotine, cotinine (17-19), y-(3-pyridyl)-Y-oxo-N-methylbutyramide (18), N -nitrosonomicotine (42), the nicotinamide nucleotide analogues of nicotine and cotinine (43) and, most recently, the intermediate formed during the nicotine to cotinine conversion (Figure 1) (44). We have failed, despite many attempts, to obtain antibodies to another metabolite of nicotine, i.e. nicotine-N -oxide. The hapten derivatives may have been... 

N-Oxidation, e.g. 2>acetylaminofluorene, nicotinamide trimethylamine, guanethidine, chlorpromazine, in pramine. 

Figure 4 shows the elution profile of MNA, N -methylnicotinic acid, nicotinamide Al-oxide, 4-Py, 2-Py, nicotinamide, 6-hydroxynicotinamide, nicotinic acid, nicoti-nuric acid, and 6-hydroxynicotinic acid on a Dowex 1-X4 formate column (73.6 cm X 0.9 cm i.d.) (24). Gradient elution was done with ammonium formate-formic acid of various pHs and ionic strengths. Detection was performed by UV absorption at 254 nm. 

Abbreviations NaAD, nicotinic acid adenine dinucleotide NMN, nicotinamide mononucleotide NaMN, nicotinic acid mononucleotide Nam, nicotinamide NiA, nicotinic acid QA, quinoUnic acid MNA, JV -methylnicotinic acid Tg, ttigoneBine = W-methylnicotinic acid Nam N-oxide, nicotinamide iV-oxide NiA V-oxide, nicotinic acid N-oxide 2-Py. iV -methyl-2-pyridone-5-carboxamide 4-Py, JV -methyl-4-pyridone-3-carboxamide NuA, nicotinuric acid. 

Rat liver homogenates appear able to convert the nicotinainide>iV-oxide to nicotinamide (iS3). When mice were injected intraperitoneally with 12.5 mg of the radioactive nicotinamide per mouse, the N-oaddd in the urine accounted for about 40 % of the total radioactivity excreted in the urine free nicotinamide accounted for about 45 % of the excretory products, and W -methylnicotinamide and nicotinic acid together accounted for most of the remaining counts (SS4). When azaserine was injected along with the radioactive nicotinamide, the rate of excretion of the urinary metabolites was accelerated. In addition, the total excretion of nicotinamide-W-oxide in the azaserine-treated animals was found to decrease with a concurrent increase of compounds that appear to be either iW-methylnicotinamide or nicotinic acid. It appears possible from the kinetics of the excretion of the nicotinamide-iV-oxide that it might arise from DPN in the liver. On the other hand, the iV -methylnicotinamide appears not to arise as the result of the breakdown of DPN in the liver. 

In the presence of NADPH and oxygen, hepatic microsomal enzymes convert the following substrates to the corresponding N-oxides chlorpromazine, chlor-qrclizine. imipramine. nicotinamide, guanethidine, and trimethylamine. Based on limited data, it was sug sted that the formation of N-oxides might be an intermediate step in all microsomal N-dealkylations. It is now clear that although N-oxides are formed by liver microsomes, they are not obligatory intermediates in all N-dealky-lation reactions. 

The modification of cyano groups during the N-oxidation of cyanopyri-dines (p. 198) produces different results according to the position of the cyano group. Thus, with hydrogen peroxide at pH 7 5-8, picolinonitrile gives picolinamide 1-oxide (70 per cent), nicotinonitrile forms nicotinamide 1-oxide (44 per cent) and isonicotinonitrile yields isonicotinamide (45 per cent) with only 4 per cent of the oxide. The first result is ascribed to intramolecular oxidation by the peroxycarboximidic acid, the second to similar intermolecular oxidation. The small proportion of 1-oxide from the 4-isomer may be due merely to deactivation by the 4-substituent . ... 

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