Directing the Metabolism of Drugs Away from CYP450: The Use of Oxetane Rings

Treatment of health problems that accompany aging often includes pharmacotherapy. It is thus common for older adults—and, increasingly, younger adults—to be on multiple medications, either prescription or over-the-counter (OTC). With the consumption of multiple medications, drug-drug interactions (DDIs) are a concern. The site of drug-drug interactions is often at the level of drug metabolism. If a drug inhibits (or enhances) the metabolism of another, the blood level (therapeutic effect) can be decreased below the required level, or adverse effects can increase. Because most currently used drugs are metabolized via cytochrome P450-catalyzed pathways, drug discovers seek drugs that are metabolized by alternate pathways. Medicinal chemists have come upon a strategy—the incorporation of oxetane rings in the drug structure—that increases the likelihood that a drug will not be metabolized via CYP450. The same modification gives other desirable physical properties to the molecule. Although there are no guarantees that there will be fewer DDIs or an absence of other unexpected problems, the strategy could pave the way for new drugs that are safer and easier to use with concomitant medications.