Lipophilic inhibitors

Factors Influencing NPYR Formation. The major factors which influence the formation of NPYR in cooked bacon have been well documented ( , ) and include the method of cooking, frying temperature and time, nitrite concentration, ascorbate concentration, preprocessing procedures, presence of lipophilic inhibitors, and possibly smoking. 

It is known that peroxynitrite is able to induce DNA strand breakage, which activates nuclear enzyme poly(ADP ribose) synthase (PARS). Szabo et al. [257] showed that the inhibition of PARS by oral treatment with lipophilic inhibitor 5-iodo-6-amino-l,2-benzopyr-one delayed the onset of arthritis in rats. It is possible that infrared pulse laser therapy can be useful for the treatment of RA patients [258]. 

The structure shown in Fig. 10.6 also suggested another approach to alter the structure of (12) to generate a lipophilic inhibitor of TS. The hydrophobic cavity filled by the aromatic ring of the para-aminobenzoyl group could be filled instead by a substituent attached to position 5 of the quinazoline nucleus. Four different 5-substituted 2-methyl-4-oxoquinazo-lines were made to test this idea, and one of these (18) was a 1 /llM inhibitor of human TS (66). 

The next selection criterion concerns the polarity of the selected cavity. In the most favorable case, it should contain hydrophobic residues to favor the design of lipophilic inhibitors. The addition of hydrophobic substitutions (taking care to ensure their solubility) is an effective way of improving the potency of an inhibitor thanks to the hydrophobic effect. It has been shown that electrostatic interactions are important for the rate of association, but not for the stability of protein complexes [20], Furthermore, electrostatic interactions are weakened by the high dielectric constant of water. It might therefore be more difficult to identify inhibitors that bind tightly to the target cavity when it is essentially polar. 

Pouchus, Y.F. et al., Specificity of the test based on modification of cell morphology for detection of lipophilic inhibitors of protein phosphatases, Toxicon, 35, 1137, 1997. 

Some notable backbone differences can be found between the early X-ray structures ISTD and 2STD obtained at low (pH 4.5, pH 5.1) and those obtained later at neutral pH (7.5-8) (3STD-7STD), which can be attributed to the pH differences. Site-directed mutations (see below) support the assumption that these differences affect the lipophilic inhibitor recognition. 

Proton Pump Inhibitors and Acid Pump Antagonists retinoid X receptor (RXR) and is also activated by various lipophilic compounds produced by the body such as bile acids and steroids. PXR heterodimerized with RXR stimulates the transcription of cytochrome P450 3A monooxygenases (CYP3A) and other genes involved in the detoxification and elimination of the... 

Cleaning solution formulations may include one or more deposit removers, plus an appropriate corrosion inhibitor (to protect exposed metal). An antifoam and often a wetting agent [e.g., an alkylarylpoly-ethoxy alcohol with a 12-15 hydrophilic-lipophilic balance (HLB) to improve detergency and solubilization] may also be added. 

Evidence exists that the relative solubility of amines and inhibitors in heterogeneous oil-water systems could be decisive in formation of nitrosamines and blocking these reactions, Nitrosopyrrolidine formation in bacon predominates in the adipose tissue despite the fact that its precursor, proline, predominates in the lean tissue (5,6,7). Mottram and Patterson (8) partly attribute this phenomenon to the fact that the adipose tissue furnishes a medium in which nitrosation is favored, Massey, et al, (9) found that the presence of decane in a model heterogeneous system caused a 20-fold increase in rate of nitrosamine formation from lipophilic dihexylamine, but had no effect on nitrosation of hydrophilic pyrrolidine. Ascorbic acid in the presence of decane enhanced the synthesis of nitrosamines from lipophilic amines, but had no effect on nitrosation of pyrrolidine. The oil-soluble inhibitor ascorbyl palmitate had little influence on the formation of nitrosamines in the presence or absence of decane. 

N-Nitrosamine inhibitors Ascorbic acid and its derivatives, andDC-tocopherol have been widely studied as inhibitors of the N-nitrosation reactions in bacon (33,48-51). The effect of sodium ascorbate on NPYR formation is variable, complete inhibition is not achieved, and although results indicate lower levels of NPYR in ascorbate-containing bacon, there are examples of increases (52). Recently, it has been concluded (29) that the essential but probably not the only requirement for a potential anti-N-nitrosamine agent in bacon are its (a) ability to trap NO radicals, (b) lipophilicity, (c) non-steam volatility and (d) heat stability up to 174 C (maximum frying temperature). These appear important requirements since the precursors of NPYR have been associated with bacon adipose tissue (15). Consequently, ascorbyl paImitate has been found to be more effective than sodium ascorbate in reducing N-nitrosamine formation (33), while long chain acetals of ascorbic acid, when used at the 500 and lOOO mg/kg levels have been reported to be capable of reducing the formation of N-nitrosamines in the cooked-out fat by 92 and 97%, respectively (49). 

Ascorbic acid (vitamin C) is one of the body s endogenous water-soluble antioxidants. Modifications on the ascorbic acid structure have led to some very interesting compounds, such as a novel series of 3-O-alkyl ascorbic-acid derivatives. They have been found to be inhibitors of lipid peroxidation (Nihro etal., 1991). This antioxidant activity is directly related to the lipophilicity of the alkyl chain, su esting that the lipid chain may anchor the antioxidant portion of the molecule in the membrane. 

Kaneko et al. (1993) have described a group of lipophilic ascorbic-acid analogues that have been studied in cultured human umbilical vein endothelial cells that were first incubated with test drug and then exposed to lipid hydroperoxides. Although ascorbate itself did not protect the endothelial cells, derivatives like CV3611 protected. Pretreatment was necessary. CV3611 was synergistic with vitamin E. The authors concluded that these lipophilic antioxidants incorporate into endothelial cell membranes where they are effective inhibitors of lipid peroxidation. In contrast, lipophobic antioxidants were not effective in their hands (Kaneko et al., 1993). 

The phenothiazines, chlorpromazine and promethazine, have been described as inhibitors of CCU-induced lipid peroxidation at relatively high concentrations in rat liver microsomes (Slater, 1968). Structural modifications of chlorpromazine were undertaken to try to increase antioxidant activity and maintain molecular lipophilicity. The 2-N-N-dimethyl ethanamine methanesulphonate-substituted phenothiazine (3) was found to be a potent inhibitor of iron-dependent lipid peroxidation. It was also found to block Cu -catalysed oxidation of LDL more effectively than probucol and to protect primary cultures of rat hippocampal neurons against hydrogen peroxide-induced toxicity in vitro (Yu et al., 1992). 

Tarzia et al. [69, 70] have recently reported the FAAH inhibitory activity of a series of alkylcarbamic acid aryl esters. The starting point for their studies was the known serine hydrolase inhibitor carbamyl (51) that had no activity at FAAH. Replacement of the small methyl group of carbamyl (51) with more lipophilic groups and, in particular, bulky lipophilic groups resulted in increased affinity at FAAH (Table 6.6). Exploration of replacements of the naphthyl moiety revealed that replacement with a biphenyl group resulted in improved affinity and in particular, the 3-biphenylyl group proved effective... 

Karajiannis, H. van de Waterbeemd, H., The prediction of the lipophilicity of peptidomimetics. A comparison between experimental and theoretical lipophilicity values of renin inhibitors and the building blocks, Pharm. Acta Helv. 70, 67-77 (1995). 

Aungst, B. J. Nguyen, N. H. Bulgarelli, J. P. Oates-Lenz, K. The influence of donor and reservoir additives on Caco-2 permeability and secretory transport of HIV protease inhibitors and other lipophilic compounds, Pharm. Res. 17, 1175-1180 (2000). 

Guanethidine (77) was the first of a series of antihypertensive agents which act by interfering with adrenergic transmission. It was subsequently found that simple substitution of the guanidine function onto a nucleus with appropriate lipophilicity almost invariably affords such sympathetic inhibitors. 

---