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Pharmaceuticals

Small-Ring Swap Makes t-Butyl Last

Trifluoromethylcyclopropyl groups could replace tert-butyl groups on compounds that don’t last in the bloodstream

by Carmen Drahl
May 6, 2013 | A version of this story appeared in Volume 91, Issue 18

STABILIZING GROUP
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Swapping a tert-butyl group for trifluoromethylcyclopropyl could increase a potential drug’s lifetime in a patient’s bloodstream.
Structures of tert-butyl and a replacement that has increased metabolic stability.
Swapping a tert-butyl group for trifluoromethylcyclopropyl could increase a potential drug’s lifetime in a patient’s bloodstream.

Metabolic enzymes often react with certain groups on drug molecules, preventing them from lasting long enough in the body to be useful. A new replacement for one vulnerable target, the tert-butyl group, could extend molecules’ staying power (ACS Med. Chem. Lett., DOI: 10.1021/ml400045j). t-Butyls are sometimes vulnerable to cytochrome P450 enzymes in the liver. These enzymes oxidize methyl groups in the t-butyl, hastening a molecule’s excretion from the body. David Barnes-Seeman’s group at the Novartis Institutes for BioMedical Research, in Cambridge, Mass., ran into this very problem with a drug lead they were studying. They solved it with trifluoromethylcyclopropyl groups, which resemble a t-butyl but lack vulnerable methyl groups. Other researchers have tried this replacement to alter a molecule’s binding affinity for a protein, Barnes-Seeman says, but they hadn’t reported its metabolic stability. His group measured the lifetime of drug compounds in the bloodstreams of rats. Compounds with the t-butyl replacement held out longer than those containing a t-butyl—about four times as long in one case. In addition, the compounds did not lose their binding affinity for their protein target.

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