Chapter 16: Discovery of the Anti-Psychotic Drug, Ziprasidone

There is no better illustration of the principles of multi-target drug discovery than the field of antipsychotic medicinal chemistry. The first antipsychotic agents, discovered serendipitously in clinical testing, possess a plethora of pharmacological activity, primarily as antagonists of neurotransmitter receptors. Thus in selecting a pharmacological profile for a second-generation antipsychotic to address the side effects of these first drugs, we had many choices to make, settling on a combination of D₂ dopamine and 5HT₂ serotonin receptor blockade. Our strategy led us to a series of oxindoles linked to benzisothiazolyl piperazine, from which we selected ziprasidone as a novel atypical antipsychotic agent for clinical trials. Ziprasidone's favorable ratio of 5HT₂ to D₂ receptor affinity affords antipsychotic efficacy with low side effect propensity, including a weight neutral profile. Exploiting a multi-target strategy produced a successful atypical antipsychotic that benefits patients in over 80 countries worldwide.