The HMG-CoA reductase inhibitor Lipitor (atorvastatin calcium), the largest selling drug in the history of the pharmaceutical industry, was designed and synthesized in 1985 at a time when medicinal chemistry was dominated by QSAR analyses and the emerging discipline of structure-based drug design. This was prior to the dramatic change in the practice of medicinal chemistry caused by the publication of Lipinski's Rule of 5, which caused the industry to focus on property-based drug design as a way of controlling ADMET properties. Despite this, one of the key aspects of the selection of Lipitor as a development candidate was development of the relationship between lipophilicity and differential drug distribution to liver and peripheral tissues. This talk will explore the development of the understanding of the tissue selectivity of atorvastatin and other HMG-CoA reductase inhibitors in relationship to physicochemical drug properties and place this work in the context of the current practice of medicinal chemistry.

Discovery and development of Lipitor: Would anyone make this molecule today?

245th National Meeting (2013)

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