Nicotinic acid derivatives, activity

The methylxanthine theophylline (p. 326), the phosphodiesterase inhibitor amrinone (p. 132), prostacyclins (p. 197), and nicotinic acid derivatives (p. 156) also possess vasodilating activity. 

Pharmaceutically important 3-substituted-[l,8]naphthyridine-2,4-diones have been prepared by the reaction of 2-methyl-477-pyrido[2,3-r/][3,l]oxazin-4-one with active methylene compounds (Scheme 66) <1997J(P1)1487, 2003JOC4567> and by the same group via an intramolecular azadiene-ketene electrocyclization reaction of amino-nicotinic acid derivatives in a related process <2001JOC4413>. 

U-56324 (28), a nicotinic acid derivative, has hypoglycaemic activity in the 18-h fasted normal rat [173] and stimulates in vitro insulin secretion [174]. Study of the in vitro activity in membrane patches from cultured mouse pancreatic jff-cells revealed that it acts directly on ATP-sensitive potassium channels and probably has the same mechanism of action as sulphonylureas [174]. 

Sosnovskikh VY, Irgashev RA, Kodess MI (2008) One-pot three-component reaction of 3-(polyfluoroacyl)chromones with active methylene compounds and ammonium acetate regioselective synthesis of novel R -containing nicotinic acid derivatives. Tetrahedron 64 2997-3004... 

The action of anabasine is similar to that of nicotine. When the piperidine ring of anabasine is opened to produce 8-amino-8-3-pyridyl-n-valeric acid the activity is reduced, and this is also true of the corresponding lactam and the benzoyl derivative. According to De Eds myosmine is less toxic than nicotine but more active on isolated guinea-pig intestine. ... 

In the first family, the metal is coordinated by one molecule of the pterin cofactor, while in the second, it is coordinated to two pterin molecules (both in the guanine dinucleotide form, with the two dinucleotides extending from the active site in opposite directions). Some enzymes also contain FejSj clusters (one or more), which do not seem to be directly linked to the Mo centers. The molybdenum hydroxylases invariably possess redox-active sites in addition to the molybdenum center and are found with two basic types of polypeptide architecture. The enzymes metabolizing quinoline-related compounds, and derivatives of nicotinic acid form a separate groups, in which each of the redox active centers are found in separate subunits. Those enzymes possessing flavin subunits are organized as a2jS2A2, with a pair of 2Fe-2S centers in the (3 subunit, the flavin in the (3 subunit, and the molybdenum in the y subunit. 

Syntheses of naphthyridone derivatives follow the same procedures as those of quinolones, except that substituted 2-aminopyridines (Gould-Jacobs modification) or substituted nicotinic ester/nicotinoyl chloride are used instead of anilines or o-halobenzoic acid derivatives. Most of the recently introduced quinolone antibacterials possess bicyclic or chiral amino moieties at the C-7 position, which result in the formation of enantiomeric mixtures. In general, one of the enantiomers is the active isomer, therefore the stereospecific synthesis and enantiomeric purity of these amino moieties before proceeding to the final step of nucleophilic substitution at the C-7 position of quinolone is of prime importance. The enantiomeric purity of other quinolones such as ofloxacin (a racemic mixture) plays a major role in the improvement of the antibacterial efficacy and pharmacokinetics of these enan-... 

The B-group vitamin, nicotinic acid (259), was irradiated with low-intensity light at 254 nm. In aqueous solution without buffer, the bi-aryl (260) was obtained, presumably via decarboxylation to give the pyridyl anion which would attack position 6 of nicotinic acid. In aqueous acid, the substrate was photo-hydroxylated to give 2-hydroxynicotinic acid (40%). Clearly, only the cationic form was sufficiently activated for position 2 to be attacked by the solvent. Nicotinamide under the same conditions was also converted to the 2-hydroxy derivative, but the reaction was slower [161]. 

Nicotinic acid and its derivatives (pyridylcarbinol, xanthinol nicotinate, acipimox) activate endothelial lipoprotein lipase and thereby lower triglyceride levels. At the start of therapy, a prostaglandin-mediated vasodilation occurs (flushing and hypotension) that can be prevented by low doses of acetyl-salicylic acid. 

The substantial interest in the pharmacological properties of nonsteroidal antiinflammatories prompted the development of a number of pyridine derivatives with analgesic activity. Thus, treatment of the N-oxide of nicotinic acid with phosphorus trichloride followed by hydrolysis of the resulting acid chloride gives (75), a precursor to nifluminic acid (76a) (66BSF2316), flunixin (76b) (B-80MI20903) and clonixin (76c) (67NEP6603357). 

Nicotinic acid (5.18), and related derivatives such as pyridylcarbinol (5.19), xanthinol nicotinate (5.20), acipimox (5.21), given in large doses, influence the lipoprotein ratio, decreasing the concentrations of very low and low-density lipoprotein, but have no effect on HDL-cholesterol complexes. Acipimox (5.21) is a new pyrazine derivative that is 20 times more active than nicotinic acid. When first administered, the use of these agents is associated with flushing and hypotension. 

FIGURE 13-17 Structures of niacin (nicotinic acid) and its derivative nicotinamide. The biosynthetic precursor of these compounds is tryptophan. In the laboratory, nicotinic acid was first produced by oxidation of the natural product nicotine—thus the name. Both nicotinic acid and nicotinamide cure pellagra, but nicotine (from cigarettes or elsewhere) has no curative activity. 

Nicotine biosynthesis also involves the incorporation of nicotinic acid (Fig. 2.2) (Robins et al., 1987), and the availability of this moiety can be as important in nicotine accumulation as that of the putrescine-derived portion. However, the enz)une responsible for the condensation of N-methylpyrrolinium with decarboxylated nicotinic acid, nicotine s)mthase (Friesen and Leete, 1990), was measured at only a very low level of activity, quite inadequate to account for the rates of nicotine accumulation observed in cultures. The molecular analysis of low-nicotine mutants of N. tabacum suggested the presence of regulatory genes (Me 1 and Me 2) governing the expression of nicotine bios)mthesis (Hibi et al, 1994). 

In contrast to pilocarpine, arecoline acts at nicotinic receptors as well as at muscarinic sites it has been described (172) as a partial agonist at and Mg receptors. Arecoline is equipotent to its quaternary analog, iV-meth-ylarecoline, as a muscarinic agonist (172). The secondary amine, norarecoline, is a somewhat weaker muscarinic agonist than arecoline (173,174). The muscarinic activity of esters of arecaidine (the free carboxylic acid derivative... 

The term niacin refers to nicotinic acid (pyridine-3-carboxyhc acid), its amide nicotinamide, and derivatives that show the same biological activity as nicotinamide. A distinction between the two primary vitamin forms has to be considered, however, when considering some aspects of their metabolism and especially their different pharmacological actions at high doses. Structures of both vitamers and the two coenzyme forms containing the nicotinamide moiety are given in Figure 30-23. 

Nicotinamide-adenine dinucleotide (NAD diphosphopyri-dine nucleotide) and nicotinamide-adenine dinucleotide phosphate (NADP also termed triphosphopyridine nucleotide) represent most of the niacin activity found in good sources that include yeast, lean meats, liver, and poultry. Milk, canned salmon, and several leafy green vegetables contribute lesser amounts but are still sufficient to prevent deficiency. Additionally, some plant foodstuffs, especially cereals such as corn and wheat, contain niacin bound to various peptides and sugars in forms nutritionally not readily available (niacinogens or niacytin). Because tryptophan is a precursor of niacin, protein provides a considerable portion of niacin equivalent. As much as two thirds of niacin required by adults can be derived from tryptophan metaboHsm via nicotinic acid ribonucleotide... 

Besides being fundamental constituents of proteins they are the parent substances from which powerful hormones are derived, for example, adrenaline (epinephrine), noradrenaline (norepinephrine), thyroxine and related substances, 5-hydroxytryptamine (enteramine, serotonin), and the plant hormone indoleacetic acid. Tryptophan is also the precursor of the B vitamin nicotinic acid and hence of part of the important pyridine nucleotides. All three aromatic amino acids are potential precursors of other substances having powerful physiological activity, for example, many of the alkaloids. Errors in the metabolism of the aromatic amino acids in man can give rise to sometimes serious, but fortunately comparatively rare, disorders such as alkaptonuria and phenylketonuria. The numerous metabolic pathways involved in aromatic amino acid metabolism therefore make an important as well as an interesting study. 

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