New Cloak May Suit Many Drugs

A new type of temporary molecular mask could help drugs in pill form reach their destinations more efficiently, chemists reported at a poster session at this week's American Chemical Society national meeting in Boston. The cloaked molecules, called amminium salts, arise from attaching an amine to a nitrogen atom on a heterocyclic ring.

Researchers at Bristol-Myers Squibb discovered the new prodrug approach while trying to improve an experimental HIV treatment called BMS-248, which barely reached the bloodstream when taken orally. The amminium version of the drug initially was an unexpected product from an amination reaction intended to make BMS-248 more polar. Inspired by established prodrugs with N–O bonds, BMS chemists decided to try using the amminium salt, which features an N–N bond, as a prodrug—a medication that is administered in an inactive form that gets activated in the body. Sure enough, the compound delivered useful amounts of BMS-248 to the bloodstreams of rats and dogs. Bacteria in the gut cleave the salt's N–N bond to reveal BMS-248.

"In principle, any compound with a nitrogen-containing heterocycle can be aminated, and the amminium salt, provided that it is chemically stable, could be used as a potential prodrug," said Alicia Regueiro-Ren, a principal scientist in virology chemistry at BMS, who presented the work on Wednesday evening in the Division of Medicinal Chemistry.

"I have not seen this type of prodrug approach before," said Valentino J. Stella, a prodrug expert at the University of Kansas. Gut bacteria vary between species and between people, so it will be interesting to see whether these differences affect the efficiency of prodrug breakdown, he notes.

The team doesn't anticipate dramatic variations in gut bacteria, said Regueiro-Ren. "However, gut microflora can be sensitive to antibiotics," so in the future it will be important to further evaluate the prodrug technology while considering potential interactions with antibiotics, she said.