FAAH Inhibitor Could Lead to Better Treatments for Pain, Anxiety and Obesity

Daniele Piomelli and his Italian colleagues developed a chemical called URB597 with a vision that it could be the basis of drugs to treat pain, anxiety and obesity. Their vision is coming one step closer to reality.

With the announcement this week that European pharmaceutical company Organon has purchased the FAAH inhibitor program from Kadmus Pharmaceuticals, Piomelli's discovery becomes part of an accelerated effort to develop a new class of drugs that can benefit millions.

Piomelli, the Louise Turner Arnold Chair in Neurosciences and director of the Center for Drug Discovery at UC Irvine, is a co-founder of Irvine-based Kadmus, which obtained an exclusive license to the FAAH inhibitor chemical from UC Irvine in 2003.

"We're excited at the progress of the development of potential therapies using a discovery from our laboratories at UC Irvine and our collaborators at the Universities of Urbino and Parma," said Piomelli, who also is a professor of pharmacology. "This effort shows great promise - from Kadmus' work to create the FAAH inhibitor program to Organon's commitment to developing it into safe, effective pharmaceuticals."

Under the purchase agreement, Organon has acquired world-wide rights and control of all assets relating to FAAH owned or controlled by Kadmus Pharmaceuticals, which is based in the University Research Park in Irvine. These assets include several patent families owned by Kadmus, the Kadmus compound library including novel second generation FAAH inhibitors, and URB597 (also called KDS-4103), a clinical trial-ready compound under exclusive license from UC Irvine.

The purchase accelerates efforts to develop a marketable drug, Piomelli said. Drug development is prohibitively expensive. The cost of taking a drug from the laboratory to the market normally runs to hundreds of millions of dollars. A company with Organon's resources makes this process possible for the FAAH inhibitor, he said. Organon is the human health care business unit of Akzo Nobel.

FAAH is an enzyme in the body that breaks down anandamide, a neurotransmitter that is part of the brain's endocannabinoid system. Dubbed "the bliss molecule" for its similarities to the active ingredient in marijuana, anandamide has been shown in studies by Piomelli and others to play analgesic, anti-anxiety and antidepressant roles. It also is involved in regulating feeding and obesity.

The synthetic chemicals created by Piomelli and colleagues block FAAH activity, boosting the effects of anandamide without producing the "high" seen with marijuana. These FAAH inhibitors have been found to be very potent, highly selective and can be taken orally. It is believed that these characteristics, along with their novel mechanism of action, make the compounds excellent candidates for drug development.

Research on the pharmacology of the endocannabinoid system is relatively new, said Piomelli, one of world's leaders in this field. Drugs focused on this system represent growing opportunities, and a number of pharmaceutical companies, such as Organon, are invested in this effort.

"Drug discovery is a challenging process that requires dedication and cooperation," Piomelli's collaborator, said Giorgio Tarzia, a medicinal chemist at the University of Urbino. "We are delighted that our international collaboration with Piomelli's laboratory has worked out so well."

UC Irvine filed for a patent on KDS-4103 in 2002. A patent was issued in 2007.

For news of Organon-Kadmus deal, see: www.medadnews.com/News/Index.cfm?articleid=454638#

About Endocannabinoids: Endogenous cannabinoid compounds are distinctive because they link with protein molecule receptors on the surface of cells, called cannabinoid receptors. (The word cannabinoid comes from the Latin name for the marijuana plant, Cannabis.) For instance, the active component in marijuana, THC, is a cannabinoid, and these receptors are activated when a person smokes the drug.

The body's natural cannabinoids function to control a variety of activities, such as pain, mood and appetite, so they are attractive targets for drug discovery and development. Currently the only available cannabinoid-based drugs are THC and one of its many synthetic analogs. They are used to reduce nausea and stimulate appetite in cancer and AIDS patients, and recent tests have shown them effective in offering relief from Tourette's syndrome and multiple sclerosis symptoms. They produce unwanted side effects, however, such as sedation and risk of addiction. By contrast, FAAH inhibitors appear to have no such side effects.

Piomelli is considered one of world's leading researchers on the pharmacological effects of endocannabinoids. He and his colleagues have characterized key mechanisms involved in endocannabinoid formation and degradation, and discovered several experimental drugs that interfere with the functioning of the endocannabinoid system in the brain.

About the University of California, Irvine: The University of California, Irvine is a top-ranked university dedicated to research, scholarship and community service. Founded in 1965, UCI is among the fastest-growing University of California campuses, with more than 25,000 undergraduate and graduate students and about 1,800 faculty members. The second-largest employer in dynamic Orange County, UCI contributes an annual economic impact of $3.7 billion. For more UCI news, visit www.today.uci.edu.

News Radio: UCI maintains on campus an ISDN line for conducting interviews with its faculty and experts. The use of this line is available free-of-charge to radio news programs/stations who wish to interview UCI faculty and experts. Use of the ISDN line is subject to availability and approval by the university.