The statin class was first identified in the early 1970s by investigators at Sankyo who discovered that the natural product, compactin (mevastatin 1), isolated from microbial fermentations of Penicillium citrinum in a search for new antimicrobial agents, potently inhibited HMG-CoA reductase and lowered serum cholesterol levels in animals.61 Compactin (Figure 7) also effectively lowered serum total cholesterol and LDLc in heterozygous FH patients. However, development was stopped in 1980 for unknown reasons that may have been related to toxicity issues that were uncovered in longer term animal studies.51
Following the compactin lead, lovastatin 2 (Figure 7) was identified from fermentation broths from Aspergillus terreus. Lovastatin and compactin are very close structural homologs, with lovastatin containing an additional methyl group in the bicyclic decalin ring. Both compounds are administered as inactive lactone prodrugs that must be metabolized in vivo to the corresponding open hydroxy-acid forms before HMG-CoA reductase inhibition can occur.54,62 Like compactin, lovastatin effectively lowered plasma LDLc in animals and produced profound reductions in serum LDLc in heterozygous FH patients. The association between lipid lowering and HMG-CoA reductase inhibition was later shown with lovastatin to be due to an upregulation of the LDLr and the resulting enhanced clearance from plasma of excess LDLc.34 The development of lovastatin was slowed by safety considerations surrounding compactin and the perceived underlying uncertainties associated with the potential consequences of long-term cholesterol biosynthesis inhibition. Lovastatin 2 was approved by the FDA in 1987.51
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