Putative active metabolite

The drug is metabolized by N-demethylation to the putative active metabolite dimethadionc. - Dimethadione is a calcium T chiinnel blocker. Dimethadione is a water-soluble and lowly lipophilic compound and thus is excreted as such without further metabolism. 

We have speculated on but do not understand the mechanism causing the lytic activity of laetisaric acid. The active twelve carbon metabolite of laetisaric acid may poison a key enzyme in lipid metabolism or disrupt the integrity of the fungal cell membrane by insertion or dissolution as has been shown in Escherichia coli with sodium dodecyl sulfate and Triton X-100 (24 r 25). Why the C-12 molecule is most active remains to be determined. Kinetic studies of lipid metabolism and physicochemical and ultrastructural investigations of membranes treated with the putative active metabolite may answer these questions. 

Since that time, many other tricyclic antidepressants have been studied and put into use. They are all structurally related to imipramine. The active metabolite of imipramine is desipramine. This means that imipramine breaks down into desipramine in the body, and the resulting desipramine actually improves mood. Because their structures are so similar, scientists assume that they have a similar action in the body. 

To put this in perspective, the mean half-live of norfluoxetine is 20 days in a physically healthy older patient. That means it will take 100 days to achieve C ss oi ce fluoxetine has been started and 100 days to clear 97% of this active metabolite once the parent compound has been stopped. These times may be even longer at higher doses because fluoxetine has nonlinear pharmacokinetics over its recommended dosing range (i.e., autoinhibition). 

Johnston and coworkers showed that putative hepatic metabolites of PED may contribute to the in vivo inhibitory activity of this compound, although their inhibitory activity is not very strong, compared with PED. Zimniski and coworkers reported that the propyl ester of 10-(2-propynyl)estr-4-ene-17-ol-3-one was inactive as an aromatase inhibitor in vitro however, it was as potent as PED in the rat in vivo, suggesting that the ester was hydrolyzed quickly in vivo. 

Micro-organisms are readily amenable to scale up supporting the production of gram quantities of known or putative mammalian metabolites. These compounds are often invaluable as standards formetabolite identification. Inaddition, they may also be used to establish the biological activity/to.xicity profile of mammalian metabolites which are typically only available in trace amounts. 

In another study using flash-frozen liver biopsies obtained from 37 insulin-resistant, obese, nondiabetic individuals [51], it was found that hepatic DAG content in cytoplasmic lipid droplets was the best predictor of insulin resistance y = 0.80, p<0.001), and it was responsible for 64% of the variability in insulin sensitivity. Mechanistic studies showed that hepatic DAG content was strongly correlated with activation of hepatic PKCe (y = 0.67, p< 0.001), which impairs insulin signaling, and that there was no significant association between insulin resistance and other putative lipid metabolites or plasma or hepatic markers of inflammation. The investigators concluded that hepatic DAG content in lipid droplets was the best predictor of insulin resistance in humans, and the data supported the hypothesis that NAFLD-associated hepatic insulin resistance is caused by an increase in hepatic DAG content, which results in activation of PKCe. 

One notable example is the discovery of ezetimibe (63) (Fig. 24), a marketed P-lactam derivative that lowers systemic cholesterol levels by blocking intestinal absorption of cholesterol [108, 109]. A key experiment led to the identification of active metabolites of the prototype compound 62 after dosing to rats [108], which in turn led to the discovery that metabolites were more efficiently localized to the putative site of action of the drug than 62 itself. Additional studies elucidated the... 

The TAAR receptor system has also been associated with body temperature regulation on the basis of putative thyroid hormone metabolites and their synthetic derivatives (thyronamines) activating TAAR1 in rodents. However, as these effects are only observed with thyronamine concentrations several orders of magnitude above physiological levels, and as the specificity of these compounds has not been determined, the physiological significance of these observations is unclear. 

The presence of chemically reactive structural features in potential drug candidates, especially when caused by metabolism, has been linked to idiosyncratic toxicity [56,57] although in most cases this is hard to prove unambiguously, and there is no evidence that idiosyncratic toxicity is correlated with specific physical properties per se. The best strategy for the medicinal chemist is avoidance of the liabilities associated with inherently chemically reactive or metabolically activated functional groups [58]. For reactive metabolites, protein covalent-binding screens [59] and genetic toxicity tests (Ames) of putative metabolites, for example, embedded anilines, can be employed in risky chemical series. 

The structure-activity considerations at that time naturally enough focussed interest on epoxides formed at the K-regions of the carcinogenic hydrocarbons (Figure 3), but it was not until 1964 that the synthesis of such putative metabolites was achieved (46). 

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