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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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February 20, 2013

A New Old Diabetes and Obesity Drug Candidate

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Posted by Derek

Obesity is a therapeutic area that has broken a lot of hearts (and wallets) over the years. A scroll back through this category will show some of the wreckage, and there's plenty more out there. But hope does that springing-eternal thing that it does, and there's an intriguing new possibility for a target in this area. Alan Saltiel of Michigan (whose group has had a long presence in this sort of research), along with a number of other well-known collaborators, report work on the inflammation connection between diabetes and obesity:

Although the molecular events underlying the relationship between obesity and insulin resistance remain uncertain, numerous studies have implicated an inflammatory link. Obesity produces a state of chronic, low-grade inflammation in liver and fat accompanied by the local secretion of cytokines and chemokines that attenuate insulin action. Knockout or pharmacological inhibition of inflammatory pathways can disrupt the link between genetic- or diet-induced obesity and insulin resistance, suggesting that local inflammation is a key step in the generation of cellular resistance to important hormones that regulate metabolism.

Saltiel's lab had already implicated IKK-epsilon as a kinase involved in this pathway in obese mouse models, and they've been searching for small-molecule inhibitors of it. As it turns out, a known compound (amlexanox) with an uncertain mechanism of action is such an inhibitor. It's best-known, if it's known at all, as a topical canker sore treatment, and has been around since at least the early 1990s.

Administration of this selective TBK1 and IKK-ε inhibitor to obese mice produces reversible weight loss and improved insulin sensitivity, reduced inflammation and attenuated hepatic steatosis without affecting food intake. These data suggest that IKK-ε and TBK1 are part of a counterinflammatory process that sustains energy storage in the context of insulin resistance. Disruption of this process by amlexanox thus increases adaptive energy expenditure and restores insulin sensitivity. Because of the apparent safety of this drug in patients, we propose that it undergo study for the treatment of obesity, type 2 diabetes and nonalcoholic fatty liver disease in patients.

I don't see why not. The compound does seem to be absorbed after oral dosing (most of the topical paste ends up going down into the stomach and intestines), and about 17% is excreted unchanged in the urine. You'd think some sort of oral formulation could be worked out, given those numbers. It looks like a low-micromolar inhibitor, and is selective against a kinase panel, which is good news. And treatment of mice on a high fat diet prevented weight gain, while not altering food intake. Their insulin sensitivity improved, as did the amount of fat in the liver tissue. Giving the compound to already-obese mice (either through diet or genetically predisposed (ob/ob) animals) caused the same effect. Metabolic cage studies showed that increased energy expenditure seemed to be the mechanism (as you'd think - thermodynamics will only give you so many ways of losing weight while eating the same amount of food, and the obvious alternative mechanism might not be very popular).

Just how the compound does all this is somewhat mysterious:

The precise mechanisms by which amlexanox produces these beneficial effects in obese rodents have not yet been completely elucidated. Although amlexanox is known to be a mast cell stabilizer of unknown mechanism20, and depletion of mast cells may have beneficial metabolic effects59, most of the in vivo and in vitro evidence points to a role for the drug in increasing expenditure of energy while reducing its storage in adipocytes and hepatocytes. Furthermore, the lack of a phenotype in wild-type mice reconstituted with Ikbke knockout bone marrow indicates that the role of IKK-ε in bone marrow-derived cells such as mast cells and macrophages is less important than its role in other cell types such as adipocytes and hepatocytes. Although IKK-ε and TBK1 expression is elevated as part of the inflammatory program downstream of NF-κB, the kinase targets of the drug do not seem to be direct participants in the increased inflammatory program. In fact, the reduced inflammation observed in vivo with amlexanox treatment may be an indirect effect of improved metabolic disease or, perhaps, of elimination of a feedback pathway that maintains inflammation at low levels such that inflammation is permitted to resolve. Moreover, despite the fact that administration of amlexanox to obese mice restores insulin sensitivity, these compounds are not direct insulin sensitizers in vitro.

This level of unworkedoutness will surely interest some companies in taking a look at this, and if proof-of-concept can be found with amlexanox itself, a more potent inhibitor would also be something to search for. I have just one worry, though (he said, in his Peter Falk voice).

We were just talking around here about how mouse models of inflammation are probably useless, were we not? So it would be good news if, as speculated above, the inflammation component of this mechanism were to be an effect, not a cause. A direct attack on metabolic syndrome inflammation in mouse models is something that I'd be quite wary of, given the recent reports. But this might well escape the curse. Worth keeping an eye on!

Comments (12) + TrackBacks (0) | Category: Diabetes and Obesity


COMMENTS

1. Dr. Q on February 20, 2013 11:28 AM writes...

By extrapolation from the previous post on Mouse Models of Inflammation Are Basically Worthless on Feb 13th, my bet is on this failing. Non of the studies looking at anti-inflammatory drugs were able to treat diabetes. Examples include anti-Il-1b from Lilly and XOMA as well as anti-TNF therapy that never showed improvement in diabetes in a subset of diabetic patients on these drugs. Add to that the fact that it is a kinase and we all know the story of developing kinase inhibitors (that tend to always hit other kinases) in chronic disease. I am not holding my breath on this one. We have treated mouse diabetes with anti-inflammatory mechanisms several times over but mice are not humans as we get reminded every once in a while.

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2. petros on February 20, 2013 12:18 PM writes...

Is the observed activity even related to kinase inhibition? Simply looking at the Pubchem data highlights the multiple observed effects of amlexanox.

There are surely cleaner IKK inhibitors around to test that hypothesis while Domainex has IP on novel TBK1/ IKKε inhibitors. It suggests these to also have utility in other indications.

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3. In Vivo Veritas on February 20, 2013 12:37 PM writes...

Amlexanox has been available as an oral in Japan for quite some time (asthma). Nobody noticed that it causes weight loss?
My bet is that this one gets lost in translation.

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4. luysii on February 20, 2013 1:13 PM writes...

I don't know why people worry so about treating obesity, when a nearby country has come up with an efficient way to prevent it entirely. For details see --

https://luysii.wordpress.com/2013/01/24/a-solution-to-americas-obesity-problem/

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5. kinaser on February 20, 2013 3:09 PM writes...

If that molecule's acting as an IKKe inhibitor I'll eat my hat. I don't know how the referees let this one through.

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6. Anonymous on February 20, 2013 11:30 PM writes...

Well the "present addresses" of some of the authors are at GSK, according to the link. I'm sure they'll formulate it with resveratrol and make it an even more super potent weight loss, age loss, anti-diabetic, anti-hair loss drug that we'll all enjoy and invest our retirement savings in now knowing that they couldn't possibly be wrong with this irrefutable data. And we'll also invest in McDonalds just in case.

Just gotta love those low micromolar compounds........good for publication......but not much else.

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7. drpcp on February 21, 2013 12:40 AM writes...

One thing to note is that there's a reasonable amount of clinical evidence in humans on inflammation/obesity/depression, too. http://www.ncbi.nlm.nih.gov/pubmed/21485745?dopt=abstract

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8. Timo on February 21, 2013 6:28 AM writes...

Another link between obesity and diabetes lies in glucose utilization. The drug substance Dapaglifozin has recently been approved (well, at least in Europe) for treatment of diabetes. It is inhibiting glucose readsorption from the urine, and thus leads to high glucose secretion. On one hand, this lowers glucose levels in the blood, on the other hand it lowers body weight due to the fact that the calories of the excreted glucose are lost... It is not approved for the latter indication, though. But a welcome side-effect it is indeed...

And if anyone is interested: This molecule is just another triumph for natural product chemistry... ;-)

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9. Morten G on February 21, 2013 8:12 AM writes...

You want supplemental figure 7a. As best I can read that there is absolutely no difference between the body weight developments of the IKKe KO and WT mice. The drug equally depresses weight so either they are wrong about the target or the weight-loss mechanism. I am suspicious that it might have interfered with fat absorption or something similar. That conflicts with the metabolic cages data but that was 5 mice monitored over 3 days...

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10. NoDrugsNoJobs on February 21, 2013 11:43 AM writes...

You want weight loss, bring 2,4-dinitrophenol back to the market. You can lose as much weight as you like provided you avoid melting yourself into a puddle of sweat and bones. I always wondered whether some weaker analog or a compound with a maximal possible efficacy significantly below dinitrophenol could work - In other words, could the mechanism be of value?

http://en.wikipedia.org/wiki/2,4-Dinitrophenol

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11. luysii on February 21, 2013 11:44 AM writes...

#7 drpcp -- Agree ! ! There is an excellent current review of insulin resistance (which lies at the heart of the metabolic syndrome) -- Cell vol. 152 pp. 673 - 684 '13. It contains lots of references to the inflammation occurring in the adipose tissue of overweight people (fat fat == FF).

It should be noted that only 20 - 30% of the obese are insulin resistant. These appear to be the ones with the most inflammation in their fat [ Proc. Natl. Acad. Sci. vol. 110 pp. 2563 - 2568 '13 ]

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12. ralphla54 on July 7, 2013 10:12 AM writes...

A new FDA approved diet pill called Belviq just went on the market. People who take Belviq with diet and exercise were 2 times more likely to lose 5% body weight and 3 times more likely to lose 10% body weight than the people who just did diet and exercise alone. The label states that if you do not lose 5% of your body weight in 12 weeks then consider stopping. Those that do respond in 12 weeks go on to lose over 10% of their body weight in one year. Losing 22 pounds for a 220 pound man is life changing. So comments about average weight loss are misleading and incorrect since over 45% of the patients lost a significant amount of weight.
Belviq makes you more likely to succeed because it helps you feel full more quickly, reduces cravings, and helps control "food issues". It is not a 'magic pill', it merely helps people willing to diet and exercise more likely to succeed.
Belviq has a second mode of action to reduce blood sugar which may end up preventing diabetes in many cases. Diabetics and pre-diabetics who took Belviq, regardless of weight loss, saw their blood sugar numbers drop by double digit percentages. IE HbA1c -0.9 to -1.2 and fasting glucose feel -27. The cost of medications to reduce HbA1c levels exceeds the cost of Belviq. (seeArena's BloomDM phase III trial) These reductions in diabetic symptoms plus the weight loss at the same time makes Belviq a medical bargain.
With an estimated 40 million new cases of Diabetes expected over the next 10 years at a cost of over $400 billion per year to the US Health Care System, and the associated heart disease, strokes, blindness and amputations, any tool that will prevent this preventable disease from ballooning is a good tool to have. People who are borderline diabetic may benefit a great deal from Belviq whether they lose a lot of weight or just a little.

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