The discovery and development of atorvastatin, a potent novel hypolipidemic agent.

The search for potent and efficacious inhibitors of the enzyme HMG-CoA reductase (HMGRI) was the focus of considerable research in the 1980s. Building on the discovery of the fungal metabolite-derived inhibitors, mevastatin, lovastatin, pravastatin and simvastatin, a number of totally synthetic inhibitors were discovered and developed. This manuscript describes the discovery and development of one of those synthetic inhibitors, atovastatin calcium, currently marketed in the United States as LIPITOR. This inhibitor was designed based in part on molecular modeling comparisons of the structures of the fungal metabolites and other synthetically derived inhibitors. In addition to development of the structure-activity relationships which led to atorvastatin calcium, another critical aspect of the development of this area was the parallel improvement in the chemistry required to prepare compounds of the increased synthetic complexity needed to potently inhibit this enzyme. Ultimately, the development of several chiral syntheses of enantiomerically pure atorvastatin calcium was accomplished through a collaborative effort between discovery and development. The impact of the progress of the required chemistry as well as external factors on internal decision-making with regards to the development of atorvastatin calcium will be discussed.