Metabolism structural modifications, effect

Phosphonate analogs to phosphate esters, in which the P—0 bond is formally replaced by a P—C bond, have attracted attention due to their stability toward the hydrolytic action of phosphatases, which renders them potential inhibitors or regulators of metabolic processes. Two alternative pathways, in fact, may achieve introduction of the phosphonate moiety by enzyme catalysis. The first employs the bioisosteric methylene phosphonate analog (39), which yields products related to sugar 1-phosphates such as (71)/(72) (Figure 10.28) [102,107]. This strategy is rather effective because of the inherent stability of (39) as a replacement for (25), but depends on the individual tolerance of the aldolase for structural modification close... 

Many of the structural modifications that can lead to increased VD also lead to increased rates of metabolism, hence clearance, and results in a zero-sum effect on half-life. 

Table 3.2 provides further examples of chemicals that are metabolized by the Phase II pathway to more reactive species that are capable of causing toxicity by various modes, including loss of tissue function, genotoxicity, and carcinogenesis. As in Table 3.1, when possible, the effect of structural modifications on toxicity is also presented. 

Table 9.4 Examples of the effect of structural modifications on the metabolism of a lead compound...

The effect of many structural modifications of acetazolamide has been reported. Substitution on the sulfonamide nitrogen destroys in vitro activity, but activity in animals may be retained if the substituent can be removed by metabolism (39). The absence of the acetyl from the amino group greatly reduces anti enzyme activity. Acyl groups higher than acetyl (65) retain in vitro activity and diuretic activity in animals and in man but may exhibit more pronounced side effects (26). Methylation (70) gives the two isomeric prod-... 

The early pioneering work by Zeller et al. (115) on the potent MAO inhibitory effect of iproniazid—a structural modification of the tuberculostat Isoniazid—and his realization of the physiologic consequences that might arise from such a profound alteration in catecholamine metabolism, the actual confirmation by Brodie, Pletscher, and Shore (27) of the rise in brain monoamine levels following the administration of iproniazid and JB-516 (a-methylphen-ethylhydrazine), and the early euphoric effects noted by Selikoff, Robitzek, and Omstein (96) in tuberculosis patients on iproniazid therapy led Kline and his associates (67) to investigate the possible application of iproniazid in the treatment of mental depression. It was their conclusion that MAO inhibition and antidepressant effect had a causal relationship and that a new approach for the treatment of mental depression had been uncovered. The subject of the MAO inhibitors has been reviewed extensively up to 1960 by Pletscher, Gey, and Zeller (84) and by Biel, Horita, and Drukker (21) to 1963, in comprehensive reviews of the chemistry, biochemistry, pharmacology, clinical application, and structure-activity relationships of the MAO inhibitors. 

For metabolic stability screens to be most effective, the screens must be tightly linked to some means of gathering information on metabolite structure. Methods for rapidly determining metabolite molecular weight and limited structural information have improved dramatically and allow this approach to be routinely employed (Anari and Baillie, 2005 Watt et al., 2003). The goal of this type of approach is to allow the identification of metabolic soft spots which can then be altered to produce compounds with improved metabolic stability. The literature of successful structural modification to increase stability has recently been reviewed (Thompson, 2001). 

Major structural or physiological differences in the alimentary tract (e.g., species differences or surgical effects) can give rise to modifications of toxicity. For example, ruminant animals may metabolize toxicants in the GI tract in a way that is unlikely to occur in nonruminants. 

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