New Drug Stays Out of Brain, Fights Metabolic Disorders
By Anette Breindl
The typical headache for drug developers is a drug that won't cross the blood-brain barrier. But researchers from the National Institutes of Health and Jenrin Discovery Inc. hope to find success by preventing that crossing.
In the Aug. 8, 2012, print issue of Cell Metabolism, they described a drug that can reduce appetite, body weight, insulin resistance and fatty liver in mice with diet-induced obesity – all without crossing the blood-brain barrier.
The compound works by acting on peripheral endocannabinoid receptors to reverse leptin resistance. And the story of its development, senior author George Kunos told BioWorld Today, is tied to the rise and fall of Acomplia (rimonabant, Sanofi-Aventis Group SA).
First among the obesity drugs, Acomplia was able to improve practically every symptom of metabolic disorder. Accordingly, Kunos said, "great hopes" rested on the drug. That is, until the neuropsychiatric side effects showed up: anxiety, depression and even suicidal thoughts.
As a result, Acomplia was never approved in the U.S., and was withdrawn from the market in Europe after its approval. (See BioWorld Today, Nov. 17, 2008.)
Given its effects on metabolic syndrome, though – and the dearth of weight loss drugs at the time – researchers were not ready to give up on the idea of targeting endocannabinoid receptors. Those receptors exist outside of the brain as well as in it, and it appeared that at least some of Acomplia's effects were due to actions on the peripheral receptors, Kunos said, so his team hoped that "maybe we can revive the drug by limiting brain penetration."
Two years ago, Kunos and his colleagues published data on another compound – AM6545 – that shared rimonabant's beneficial effects on fatty liver, but was less effective at suppressing appetite, causing weight loss.
AM6545 differed from rimonabant itself in two ways. It did not cross the blood-brain barrier. But in addition, it worked via a somewhat different mechanism than rimonabant.
AM6545 is a so-called "neutral antagonist," a class of compounds which work by competing with the substances they block for binding to receptors. AM6545 prevents endocannabinoids from exerting their effects. But when there are no endocannabinoids around, AM6545 and other neutral antagonists have no effect because they do not themselves activate the receptors they bind to.
Acomplia, on the other hand, is an inverse agonist. It not only prevents endocannabinoids from binding to receptors, but activates the receptors to produce the opposite effect from them. Consequently, inverse agonists affect physiology regardless of whether a receptor's natural ligand is around or not.
In the work now published in Cell Metabolism, Kunos and his team tested another compound, JD5037, which is a peripheral CB1 inverse agonist.
The compound was developed by scientists at Jenrin, a startup that focuses on selectively targeting peripheral tissues. Kunos said that "They were among the first to recognize, even before rimonabant was recalled, that the neuropsychiatric side effects would be a big problem . . . the credit is theirs" for coming up with a compound that would not cross the blood-brain barrier.
In mice, JD5037 was as effective as a related compound that does act in the brain at reducing appetite, body weight, insulin resistance and fatty liver. Unlike that compound, however, it did not cause anxiety in the animals.
Kunos and his team then looked at whether these effects were in any way related to leptin. Leptin is an appetite suppressing hormone, and one attempt at developing weight loss drugs involved recombinant leptin. That attempt failed because obese individuals make plenty of their own leptin, but are resistant to its appetite suppressant effects.
In leptin knockouts, Kunos said, JD5037 "does improve insulin resistance." But it has "absolutely no effect on food intake or body weight."
The team next went on to decipher how JD5037 reduced plasma leptin levels, and discovered two mechanisms. Treatment with the experimental drug reduced leptin production, and increased leptin clearance through the kidneys. As a result, leptin levels were reduced, which restores the sensitivity of the receptors.
Kunos and his colleagues are working both on further scientific insights into JD5037's effects, and on its clinical development. They have applied for a grant for investigational new drug application-enabling toxicity studies, and the drug is already undergoing some toxicity screening. Kunos said that "we have lined up a strong group of clinical collaborators," and hopes to get into the clinic in about a year.
His lab also is testing the effects of the compound on outright diabetes. For that, the team has had to switch animal models, since mice with diet-induced obesity become insulin resistant but do not develop outright diabetes. Zucker diabetic rats do, though, and offer the opportunity to see how JD5037 affects diabetes itself. The results are preliminary and have not yet been published. But so far, Kunos said, they look "promising."
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