Atorvastatin 6 (Figure 7) is a synthetic statin that contains an unusual penta-substituted pyrrole ring in place of the hexahydronaphthalene found in the early statins. The rationale for optimization employed a combination of insights from molecular modeling and hypothesis-based chemistry to define key structure-activity relationships.63 The genesis of the atorvastatin pyrrole core developed (Figure 9) from early observations that the complex hexahydronaphthalene system could be replaced with a simpler, achiral ortho-biphenyl moiety as in 18 and still retain HMG-CoA reductase inhibitory activity similar to that of the fungal metabolites. From this observation, it was proposed that suitably substituted pyrrole analogs, e.g., 19, might exhibit similar activities. Initial work focused on incorporating small aliphatic substituents at R5 and led to the first early leads 20a and 20b (Figure 9) with submicromolar potency. The addition of more bulky groups such as cyclic aliphatic rings or aromatic groups at R5 reduced activity. However, both 20a and 20b were about 20-fold less potent than mevastatin (IC50 = 0.03 mM) after hydrolysis of the lactone to the corresponding hydroxy-acids.

Modeling comparisons of 20b versus 18 suggested that additional hydrophobic groups at R3 and R4 may be required for increased potency. The symmetrical dichloro (21a) and dibromo (21b) derivatives achieved the desired potency, and lowered lipid levels in animals comparable to mevastatin. However, these compounds were toxic in preclinical testing. In contrast, the unsymmetrical 3-phenyl-4-carboethoxy derivative 21c had greater potency than 20a. Further optimization of 21c with a short, focused series identified the anilide 21d with low nanomolar potency, about fivefold better than mevastatin, after hydrolysis to the corresponding hydroxy-acids. Chiral syntheses of both enantiomers demonstrated that all of the activity resided in the one (R,R, + )-stereoisomer shown. In several animal species, 21d was found to be more effective at LDLc lowering than lovastatin. Atorvastatin 6 (Figure 7) was eventually selected for development as the calcium salt of the open hydroxy-acid analog of 21d, and atorvastatin became the first totally synthetic statin to enter clinical development.63

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