Mechanism of Action of Peripheral CB1 Inverse Agonists Suggests Potential Clinical Utility in Metabolic Disorders
PHILADELPHIA, Sept. 11, 2013 (GLOBE NEWSWIRE) -- Research published in Nature Medicine and Journal of Hepatology by scientists at the National Institutes of Health using JD-5037, the best-in-class peripheral CB1 inverse agonist from Jenrin Discovery, LLC has illuminated the mechanism of action for this class of drugs, providing a rationale for the potential therapeutic benefits seen when only peripheral endocannabinoid receptors are inhibited.
Data published in Nature Medicine reveal that blockade by JD-5037 of CB1 receptors on inflammatory cells infiltrating the pancreas prevented the death of insulin-producing beta cells by macrophage-derived cytokines. In a weight loss-independent rodent model of human type 2 diabetes, chronic treatment with JD-5037 improved glycemic control, and delayed the development of diabetes (Sept 2013, Vol. 19, 1132-1140)
A separate study published in the Journal of Hepatology demonstrated that chronic treatment of obese mice with JD-5037 reduced body weight and reversed hepatic steatosis and insulin resistance. These effects are mediated by CB1 receptor-dependant blockade of bio-active long-chain ceramides in the liver (http://onlinelibrary.wiley.com/doi/10.1002/hep.26606/abstract).
"These insights on the MOA of CB1 in peripheral tissues further our belief in the potential clinical value of JD-5037 for patients with diabetes, NASH, and other disorders," said John McElroy, PhD, President and CSO at Jenrin Discovery.
Senior author and NIAAA scientific director George Kunos, M.D., Ph.D. stated, "JD-5037 was an ideal molecule to test whether the blockade of peripheral CB1 receptors on pancreatic macrophages might explain the anti-diabetic efficacy of this class of drugs. Results in pre-diabetic animals suggest the potential to slow and even reverse disease progression."
About CB1 and JD-5037
The CB1 receptor, a subtype of the endocannabinoid cell membrane receptors, is expressed in the brain, adipose tissue, skeletal muscle, liver, pancreas, and kidney. Endocannabinoids are natural messengers that help regulate many biological functions. While previous efforts to block the CB1 receptor (e.g., rimonabant) caused psychiatric side-effects, scientists have shown that selectively blocking the receptor with a peripherally restricted CB1 inverse agonist, such as JD-5037, can retain the benefits of improved lipid levels and glycemic control, increased fat metabolism, and decreased fatty liver without negative CNS side effects.
JD-5037, Jenrin's most advanced peripheral CB1 inverse agonist, is completing IND-enabling studies and has the potential to be broadly useful for the treatment of Type 2 diabetes, non-alcoholic steatohepatitis (NASH), and other metabolic disorders. The program is currently available for out-licensing.
About Jenrin Discovery, LLC
Jenrin Discovery (www.jenrindiscovery.com) is a privately held biotech company developing a small molecule drugs targeting peripheral tissues. Jenrin's peripherally restricting technology and know-how modifies compounds to prevent transfer across the blood-brain barrier. The redesigned drugs retain pharmacological and other essential properties, with greatly reduced risk of psychiatric and neurological side effects. The company's funders include Research Corporation Technologies, Themelios Venture Partners, Ben Franklin Technology Partners of Southeastern Pennsylvania and BioAdvance.