Discovery and development of Lipitor (atorvastatin calcium)

MEDI 158

Bruce D Roth, Department of Chemistry, Department of Chemistry, Pfizer Global Research and Development, 2800 Plymouth Rd, Ann Arbor, MI 48105
Atorvastatin calcium, currently marketed in the United States as LIPITOR, was the first totally synthetic inhibitor of HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis, to be marketed as a single stereoisomer. This inhibitor was designed based on molecular modeling comparisons of the fungal metabolites and other synthetically derived inhibitors. In addition to development of the structure-activity relationships that 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 close collaboration between discovery and development chemists. The impact of the progress of the required chemistry as well as external factors on internal decision-making with regards the development of atorvastatin calcium will be discussed.