Fluvastatin

Fluvastatin 5 (Figure 7) was discovered at about the same time as atorvastatin 6 and contains a disubstituted indole core in place of the hexahydronaphthalene found in the fungal fermentation products. In contrast to atorvastatin, fluvastatin has an unsaturated E-heptenoic acid side chain. Some detailed structure-activity data for the optimization process used to identify fluvastatin have been reported.64

Also, attracted by the reported efficacy of 18 (Figure 9), several potential replacements for the decalin ring of compactin, including poly-substituted imidazoles, naphthalenes, indenes, and indoles, were explored, leading to the identification of the N-methyl indole 22a with activity comparable to compactin (Figure 10). The introduction of small bulky indole N-substituents identified the N-zïo-propyl group of fluvastatin 22c with optimal potency (IC50 = 0.007 mM), whereas the incorporation of larger groups in 22d-22f gave significantly less activity.

Structural variations of the 4-fluorophenyl group in 22c, as shown in 23a-23i, demonstrated that one or more ortho or meta methyl groups in addition to or in place of the 4-fluoro substituent gave analogs 23a-23c, with slightly better or nearly comparable activity as 22c. For example, the combination of 2-methyl and 4-fluoro substituents in 23a resulted in twice the potency of the singular 4-fluoro substituent in 22c and fourfold more potency than the 2-methyl group alone in 23g. Incorporating bulkier electron-withdrawing groups (23f) or more electron-rich or polar para substituents (23h and 23i) generally produced weaker activity. Similarly, a few aliphatic and alkoxy groups were explored in the benzo-fused ring of the indole, and none was more active than the unsubstituted indole in 22c.

Two structure-activity relationship results were generated from compounds 24 and 25 (Figure 10). The reduced dihydro derivative 24 (IC50 = 0.114 mM) was nearly 20-fold less active than 22c, demonstrating the importance that the unsaturated E-heptenoic acid contributed to potency. Conversely, compound 25 (IC50 = 0.002 mM), that switched the relative orientations of the zio-propyl and 4-fluorophenyl groups, was three times more potent than 22c, suggesting an unexpected symmetry to the enzymatic binding sites of these indole derivatives.

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