New class of compounds may have potentially widespread use in basic research and drug development

Scientists from The Scripps Research Institute have identified a class of compounds that could be a boon to basic research and drug discovery.

 
"We can make these modifications in just two chemical steps, which is a great advantage," says Research Associate Alexander Adibekian (left), shown here with co-authors Professor Benjamin Cravatt (center) and Research Associate Brent Martin.

In a new study, published online in Nature Chemical Biology on May 15, 2011, the researchers show the new compounds powerfully and selectively block the activity of a large and diverse group of enzymes known as "serine hydrolases." Previously discovered serine hydrolase-blocking compounds have been turned into drugs to treat obesity, diabetes, and Alzheimer's disease, and are currently in testing as treatments for pain, anxiety, and depression.

"There are more than 200 serine hydrolases in human cells, but for most we've lacked chemical inhibitors of their activity," said team leader Benjamin F. Cravatt III, professor and chair of the Department of Chemical Physiology at Scripps Research and a member of its Skaggs Institute for Chemical Biology, "so we've had only a limited ability to study them in the lab or to block them to treat medical conditions. This new research allows us to greatly expand our list of these inhibitors."

A Scaffold on Which to Build

Hints from previous work by the Cravatt lab and other groups led the team to investigate a group of molecules known as ureas for their ability to inhibit serine hydrolase activity. In initial tests using recently advanced techniques for measuring enzyme-inhibition strength and specificity, the Scripps Research scientists found that molecules known as 1,2,3-triazole ureas could powerfully inhibit some serine hydrolases without affecting other enzymes.

In the next set of tests, the team synthesized a basic "scaffold" of 1,2,3-triazole urea, and found that it inhibited many more serine hydrolases – still without affecting other enzyme classes – than did an existing broad inhibitor known as a carbamate. The team then began modifying the scaffold compound to refine its inhibitory activity to specific serine hydrolase targets.