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Aug 19, 2010
 |  BC Innovations  |  Cover Story

Peripheral CNR1 antagonists to the fore

In the three years following an FDA panel recommendation against approval of sanofi-aventis Group's Acomplia rimonabant to treat obesity due to severe neurological side effects, centrally acting inhibitors of

cannabinoid CB1 receptor have all but disappeared from development. Now, researchers at the NIH and Northeastern University have taken the CNS out of the equation by showing that a peripheral inhibitor of the receptor treated obesity and related metabolic disorders without eliciting neurological side effects in mice even though it could not enter the CNS.1

The NIH group is now working with Jenrin Discovery Inc., which has a number of peripheral cannabinoid CB1 receptor (CNR1) inhibitors in preclinical development. The company hopes to select a lead compound to treat diabetes or liver disease.

CNR1 is expressed in the brain, where it regulates appetite, and in peripheral tissues such as the liver, pancreas, skeletal muscle and fat, where it regulates lipogenesis and other metabolic processes. A number of pharma companies developed brain-permeable CNR1 inhibitors for obesity, including rimonabant and Merck & Co. Inc.'s taranabant

(MK-0364). The problem was that the efficacy of the compounds could not be separated from severe CNS side effects. As a result, all of the inhibitors had been discontinued by 2008.

But also that year, clues began to emerge that CNR1 inhibitors may not need to cross the blood brain barrier to elicit therapeutic effects. Researchers led by George Kunos showed that liver-specific knockout of Cnr1 protected obese mice from diet-induced insulin resistance, hepatic steatosis (fatty liver)...

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