The return of two old targets?

Once the physiological function of an enzyme is understood, a rationale for therapeutic intervention often becomes apparent. It is much harder to find synthetic inhibitors with the required specificity and safety. Preclinical biological data packages are not always predictive of the response in humans. Rational targets, therefore, go in and out of fashion according to the status of candidate drugs. Acyl-CoA:cholesterol acyltransferase and squalene synthase inhibitors have been studied for many years, but safety and early clinical data did not support progression. In recent months, data have become available on new compounds for each target which suggest a way forward. This editorial reviews the difficulties and potential for each target in the light of recent reports.