Metabolic deactivation

Volume I). The most rapid metabolic deactivating reaction is oxidation to the bioinert C15 oxo prostaglandins. Converting the latter to a tertiary methyl carbinol led to the desired orally active gastric antisecretory agents. 

Scheme 1. Metabolic deactivation of fluticasone propionate (1) in the liver.

Selection of the final candidate for development was based on various properties. In addition to the therapeutic index, availability, synthesis, and softness (the rate and easiness of metabolic deactivation) also had to be considered. Loteprednol etabonate (4, chloromethyl 17a-ethoxycarbonyloxy-l lp-hydroxy-3-oxoandrosta-1,4-diene, 17P-carboxylate 1 A1, R = CH2C1, R2 = COOC2H5,... 

De Flora S. 1978. Metabolic deactivation of mutagens in the Salmonella-microsome test. Nature 271 455-456. 

Petrilli EL, De Flora S. 1978a. Metabolic deactivation of hexavalent chromium mutagenicity. Mutat Res 54 139-147. 

The maternal capacities that provide a homeostatic environment and metabolic deactivation of potential toxicants, along with the repair and regenerative capabilities of the embryo/fetus, are believed to impart a threshold phenomenon to developmental toxicity. The supposition of a threshold implies that a maternal dose exists at which a toxicant will elicit no adverse effect on the conceptus. This is in contrast to the threshold principle of carcinogenesis, which assumes that exposure to any amount of carcinogen, even a single molecule, can potentially lead to cancer. 

Serious drawbacks of the natural occurring compounds however do not allow their general use in therapy. The rapid metabolic deactivation21-25 and the too wide range of activity are the main problems which have to be overcome. The development of other clinical applications awaits further progress in prostanoid research and this meant a challenge to the synthetic chemists to develop chemical total syntheses which could effectively compete with biosynthesis and which could be easily modified in order to prepare analogs with improved selectivity and stability to metabolic deactivation. 

Keefer LK, Anjo T, Heur YH, et al, 1987. Potential for metabolic deactivation of carcinogenic N-nitrosodimethylamine in vivo. lARC Sci Publ... 

Different kinds of hydrolytic metabolism are relevant to the deactivation of, e. g. thromboxane A2 [55] (Scheme 4.24), prostacyclin [56[ (Scheme 4.25), and many nucleoside-based pharmaceuticals [57[- The first step of the metabolic deactivation of cortisol is oxidation of the lip hydroxy group to a carbonyl function, presumably by a reaction mechanism involving hydride transfer [58[ (Scheme 4.26). 

Compounds which were fluorinated at C-24 (20), C-26 (21), or C-23 (22), prevented the hydroxylation reactions that lead to metabolic deactivation of the vitamin D. ... 

Loteprednol (26) was selected for development based on various considerations including the therapeutic index, availability, synthesis, and "softness" (the rate and easiness of metabolic deactivation). Early studies in rabbits (106, 109) and rats (110) demonstrated that, consistent with its design, (26)isindeed active, is metabolized into its predicted metabolites (27, 28) (Fig. 15.10), and these metabolites are inactive (105). The pharmacokinetic profile of loteprednol indicated that, when absorbed systemically, it is rapidly transformed to the inactive metabolite (27) and eliminated from the body mainly through the bile and urine (110, 111, 113). It did not affect the intraocular pressure in rabbits (109), an observation confirmed later in various human studies (Fig. 15.12) (119). Consistent with the soft nature of this steroid, systemic levels or effects cannot be detected even after chronic ocular administration (120). 

The 19-azido (93) and 19-methylthio (94) 4-androstene-3,17-diones have been found to be potent competitive reversible inhibitors (Kj = 5 nM and /fj = 1 nM respectively, for (androstenedione) = 25 nM). The same workers also discovered that 19-methanesulphonylthioandrostene-3,17-dione (95) inactivates AR in the presence of NADPH and Oj, although no kinetic or inhibitory data were presented [213]. The interaction of (94) with the active site was found to differ from that of (95) in that the latter displaces the substrate steroid from its binding site and on metabolism deactivates the enzyme, whereas (94) interacts with the substrate binding site but also with the haem-iron complex via a postulated coordinate bond. The differences in binding were deduced by examination of the ultraviolet spectral changes induced by the addition of the two inhibitors to the AR enzyme preparation. 

The metabolic deactivation offlunitrazepam illustrated in Fig. 8-20 proceeds via demethylation and hydroxylation to give desmethylflunitrazepam, an active metabolite, and 3-hydroxyflunitrazepam. However, these two compounds are only important in blood analysis. The main metabolite in the urine is the 7-amino-derivative, which is sometimes present as the acetamido-compound. 7-Aminodesmethylflunitrazepam and 3-hydroxy-7-acetamidoflunitrazepam are also relevant flunitrazepam metabolites in the urine, but the starting substance itself does not normally appear. Approximately 10% of the dose is excreted via the bile with the feces. 

The metabolic deactivation of MDE proceeds via dealkylation to MDA and piperonylacetone, leading to the formation of a hippuric acid derivative. As well as these three metabolites, 3,4-dimethoxy- and 4-hydroxy-3-methoxyamphet-amine derivatives can be detected in the urine [10]. An analogous route for MDMA has also been described [52]. 

Chlormethiazole is metabolized in the liver at a high rate and is excreted in the urine mainly in the form of inactive metabolites. The proportion of unchanged substance is usually less than 5% of the applied dose. The biological availability therefore increases in patients with impaired liver function. Metabolic deactivation proceeds by stepwise oxidation of the chloroethyl group to 4-methylthiazole-5-acetic acid. Other routes are shown in Fig. 8-36. The main metabolites in urine are the 1- and 2-hydroxyethyl derivatives. Some metabolites are excreted as conjugates [44],... 

A year previously, Burstein, Dorfman and Nadel [40] had found that metabolic deactivation of hydrocortisone in man occurred through 6/S-hydroxylation. It occurred to the reviewer that such metabolic deactivation might be prevented by 6-methylation. To this end 6a-methylethisterone was prepared by Adams, Ellis, Petrow and Stuart-Webb [41] and found [42] to be c. 6-5 times more potent than the parent ethisterone (XVI) in the Clauberg assay (p. 183). Extending the series. Barton, Bum, Cooley, Ellis, Petrow and Stuart-Webb [43] prepared dimethisterone (XXIV), which is the only derivative of testosterone presently in use. In addition, (XXIV) is surprisingly effective in endometrial carcinoma [44]. 

Ethers are less significant than esters in biological systems, like esters with organic adds ethers are much less polar than the parent alcohol, and ether formation may be used as a metabolic deactivation reaction such as in the metabolism of adrenaline to metanephrine (Fig. 5.20) which removes its biological activity. 

These drugs maintain structural similarities to adrenaline and follow on from isoprenaline which is a more potent agonist than adrenaline at p receptors. However, isoprenaline has potent effects on both Pi and P2 receptors and thus has undesirable effects on the heart. The agents that have replaced it are selective for the P2 receptor and have reduced rates of metabolic deactivation. They are used in treating asthma and bronchospasm. 

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