Potent structural variations

In contrast to these disappointing early findings, several highly potent epothilone analogs with structural variations in the C9-C11 trimethylene region have been described more recently, some of which have also been found to exhibit favorable in vivo pharmacological properties. 

The SARs of compounds structurally related to morphine are outlined in Table 24.2. A number of the structural variations on morphine have yielded compounds that are available as drugs in the United States. The most important of these agents, in terms of prescription volume, is the alkaloid codeine. Codeine, the 3-methoxy derivative of morphine, is a relatively weak p agonist, but it undergoes slow metabolic 0-demethylation to morphine, which accounts for much of its action. Codeine also is a potent antitussive agent and is used extensively for this purpose. 

Figure 9-11 Application of SAR-by-NMR to the development of a metalloprotease inhibitor. Screening of a library of small organic compounds revealed acetohydroxamic acid and 4-phenylpyrimidine as weakly binding to stromelysin (Kd 17 mM and 20 mM, respectively) at adjacent sites left, the contour lines symbolize the protein surface). After introduction of an appropriate linker (shown in grey, right panel) and systematic structural variations, a highly potent inhibitor of stromelysin and gelatinase A (IC50 = 25 nM, right) could be developed within a few months. [37], [38].

Comparing the structures of nicotine and epibatidine to the first neonicotinoid, imidacloprid, one may suspect the example of a consequent further development of a highly potent lead compound from the natural products pool (Fig. 8.42). This is indeed not the case. Nicotine has been used as an insecticide for more than a hundred years. However, Izuru Yamamoto s structure variations in the 1960s did not result in any promising active substances. [135] Epibatidine, the nAChR agonist from a poisonous frog skin, which could have served as a pharmacophore template, had still not been discovered at the time when neonicotinoids were being developed. 

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