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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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September 24, 2009

Obesity: Hope Springs Eternal (Summer 2009 Version)

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Posted by Derek

Some very interesting papers from the obesity research field have been published in the last few months. There have been a number of these over the years, and (as is widely apparent), none of them have quite lived up to their initial promise. This latest mechanism has been written up by both academic groups and industrial ones, which leads to some speculation about the state of the field - read on.

First, some background: GLP-1 (glucagon-like peptide 1) is a very important metabolic regulator. Peptides that mimic it at its receptor (but with a longer half-life) are marketed diabetes therapies (Byetta (exenatide), liraglutide, and others), and the DPP-IV inhibitors, like Januvia (sitagliptin) and its upcoming competition do something similar by inhibiting the enzyme that normally breaks the peptide down.

In addition to glycemic control, GLP-1 and related ligands also have complex effects on appetite in rodent models. These are still being unraveled, and depend on which peptide you use, and whether it's given out in the periphery or into the brain. More than one mechanism seems to be involved.

Glucagon is another key player in regulating glucose - it's another peptide hormone with its own receptor, and its most noticeable effect is as sort of counterweight to insulin in glucose control. It stimulates the liver to break down glycogen and release glucose, among other things, and people have tried (so far, without success) to develop glucagon blockers as a treatment for diabetes.

There are several other important signaling peptides in this space, such as GLP-2 and oxyntomodulin, and it's been clear for a few years now that there's some sort of opportunity to come up with a mixed-activity ligand that might hit these various piano keys to produce the right chord. (Several such have been reported in the diabetes field). These peptides are all part of the gut-to-brain signaling system, which is rather complex and has been the target of a number of obesity research programs over the years. Signals for satiety, hunger, glucose handling, and energy expenditure are all tangled together there, but in ways that we don't understand well, so it's been a very attractive minefield. For the most part, compounds targeting these systems have been stabilized forms of peptides themselves, and thus have to be given by injection. Small-molecule ligands for these receptors have been much harder to come by.

Now for the new results. A team from Indiana, Kentucky, and Cincinnati reported back in July in Nature Chemical Biology that dual agonist peptides acting at both the GLP-1 and glucagon receptors do a tremendous job on obese rodents. (Here's a PDF from one of the authors). They took two of them into diet-induced-obese mice, and saw very significant weight loss, which appears to have been almost entirely body fat, and was driven by simultaneously higher energy expenditure coupled with lower food intake.

There would indeed be a market for that, and you can bet that the possibility hasn't escaped the metabolics groups at the large companies. At almost the same time, in fact, a group at Merck published a very similar study in obese mice with their own dual-agonist peptide, and saw the same sort of thing: weight loss, improvement in metabolic markers, decreased fat mass, the whole deal.

Now, what does all this mean for the state of the art? Merck wouldn't publish such interesting results without a good reason - you have to wonder if they're far enough along that they felt safe talking about such things, or (alternately) if there are clear problems with the approach that will keep this mechanism from ever being used. Nothing's shown up in the open literature about the latter possibility, as far as I can see. So the race would appear to be on. Is it?

Comments (19) + TrackBacks (0) | Category: Diabetes and Obesity


COMMENTS

1. Retread on September 24, 2009 9:37 AM writes...

Well and good, but consider this -- the average annual calorie consumption in this country is roughly 1,000,000 calories. Also note that the food calorie is the kiloCalorie of the chemist. Plenty of people don't count calories and maintain a constant weight from year to year. This implies that there are multiple redundant systems present to maintain weight.

The animal literature is full of negative effects on body weight when a supposed orexic or anorexic peptide is knocked out --
neuropeptide Y for example [ Nature vol. 381 pp. 377 - 378 '96
]. Interesting to me as a neurologist, but rather tangential, is that the animals have convulsions. No one would have predicted this from 'first principles'.

Permalink to Comment

2. Soo Desu Ne? on September 24, 2009 1:10 PM writes...

Hello. I stumbled on the website. Thanks derek. lot of talent here.

I don't think obesity needs to be worked on, it is one of those nonissues. Any thoughts to paring down your industry to get the next trillion spent on drugs to get a us further down the road?

Oxyntomodulin looked misspelled. It wasn't and I'm mollified.

Paragraph #2 says if a trillion gets us to 2015, let's make it get us to 2020, that's all.

Paragraph #3 says it was not spelled wrong; it has a molecular wt. of 4421.9. Someone mentioned the Time Cube. It is an Internet joke. There are a few. I had not heard of itbefore. I looked it up. I did not look up what statins are doing to my muscles. I like atrophy. I hope you do to, but you might like how flu chooses who to kill better, in spite of heroic medical efforts. That's really interesting. This is paragraph #5. I'm working on the retort used by Obama-"I was black before the election." A viable argument?
I'm psychic, I'm a witch, and how long have you been a schizophrenic? See? No? Okay, how long have you been black? well, I am trying to explain the answer to your question, which is, "Is America still pretty racist?" Or, "I work against schizophrenia". Don't do me any favors, Derek. My thesis is that experience is infinitessimal compared with events, not to mention the racism making it subjective as a memory. So, leading with intelligence, intelligent and psychic is necessary and sufficient. What I don't know I get by telepathy, not experience. Long paragraph and I muted my point.

My point's time-related; my new-found colleague at the Time Cube, if irrational time-related claims are going to be made, let's cut our psychic teeth:

10,000 will be, ...

Let 10,000 be a MW = 24 hours. 0.44219 x 10,000 is ...

I am messing this up as if we are connected and you are used to mentally bashing competitors. Come on Arkansaw!

0.44219 x 24 = 10.61256. Yeah, it's the ten o'clock hour. 0.61256 of an hour is 36, 37 minutes. Plus five so I don't cut myself, it is now 11:10. I am a half-hour late, but closer, such that it is a billion-to-one shot and I hit it, depends upon the divisions of a day. This psychic stuff is hard.

But, you promoted experience. It think you have a vested interest in saying that. That's what a PhD is, and you happen to have one, so, ...

Any way, it is time-stamped; it is before the effect, so it is a cause; it is random or determinate. I leave as an exercise to calc out today's date as amolecular weight. What's today's chemical, in the 10,000 range?

Permalink to Comment

3. SteveM on September 24, 2009 3:26 PM writes...

Derek,

Re: "...saw very significant weight loss, which appears to have been almost entirely body fat, and was driven by simultaneously higher energy expenditure coupled with lower food intake."

Oh, in other words if people simply exercised more and ate less, they would experience significant weight loss?

I hope the perverse irony of spending billions to develop expensive drugs to induce behavior people could/should be taught on their own is not lost on you.

P.S. Regarding the genetic arguments, how come Europeans (same genetic stock) are not as fat as Americans? Have they developed the wonder drug first without our knowing it?

P.P.S. Interesting mind excursion by Soo Desu Ne? I'll have to have a few martinis and then try to parse it out...

Permalink to Comment

4. Harry on September 24, 2009 3:28 PM writes...

Dear Mr/MS Soo- I have one word for you, just one word....Thorazine!

Lots of it, and sooner, rather than later.

BTW- you diidn't get your PhD from Kryghystan (sp?) did you?

Permalink to Comment

5. Chrispy on September 24, 2009 3:42 PM writes...

Have we forgotten leptin so soon?

We actually already have a few diet drugs which work great. Amphetamines take the pounds right off and used to be commonly used for this (side effects and dependence, of course, were/are an issue). Thyroid hormone also does a bang-up job of boosting metabolism -- I'm not sure why it is not used for weight loss (anyone know?).

Permalink to Comment

6. Retread on September 24, 2009 3:58 PM writes...

Thyroid hormone (in excess) is very hard on the heart. One of the medical reasons to get the pounds off is to give the heart a break. Recall that president Bush I and his wife both developed a cardiac arrhythmia (atrial fibrillation) due to a (spontaneously) overactive thyroid gland. Bush I wasn't overweight.

Permalink to Comment

7. Soo Desu Ne? on September 24, 2009 5:02 PM writes...

@Harry,

You are recommending Thorazine on a website called "In the Pipeline", the meaning of which is to accept without qualification the dictates of Big Pharma. Health care is a disgrace and quite a current event. Your position is the default one and I fully expect that one fine day your little racketeers will get raked over the coals, which they so richly deserve.

My reference to PhDs is a follow-on situation from earlier in the week when the author felt the backlash for claiming lack of a PhD caused an accident. He said he needed to make his position clear. He really needed to do some fast stepping around the issue. I don't see any reason to drop it. I have B.A.

I first found this website yesterday. I stayed up till two. I'm punchy. But, I have a message.

http://sbillinghurst.wordpress.com

You think I'm crazy now, read that.

Historical losses sometimes make us falsely secure that we have already suffered for our faults.

As a chemist, you ought to be capable of writing little programs to turn out a molecule a day. Anybody can blog.

I dare to drop the human element into truth and reality, so we see, for instance, what if you have to suspend disbelief? Suppose ethanol is different from methanol. Now suppose we say that on that basis, methanol and propanol have no difference. You better believe that.

I must have made the mistake of telling the truth to liars.

The rest of us destroyed by Thorazine certainly know what your little snide remark really means: genocide.

Permalink to Comment

8. Linnea on September 24, 2009 5:34 PM writes...

This dual-activity puts me in mind of another recent obesity target, GPR119 (GDIR). Agonists at this receptor stimulate the release of both GLP-1 and GIP. There are a few therapeutics in the clinic that make use of this mechanism - Arena and Ortho-McNeill are collaborating on a program, and Metabolex and OSI also have candidates. The patents suggest that these may be small molecule therapeutics, which could provide another advantage over the current GLP-1 mimetics.

Not quite the same, but is there any overlap here?

Permalink to Comment

9. Temple on September 24, 2009 11:23 PM writes...

Time for moderated comments? :)

Permalink to Comment

10. alig on September 25, 2009 6:36 AM writes...

Word Soo dawg, thanks for keeping it real.

Permalink to Comment

11. haywarmi on September 25, 2009 11:47 AM writes...

I've always hated the argument that obesity is not a disease and we don't need to do drug discovery to treat it, just change life styles. There's been a lot of debate here everytime Derek brings up the next weight loss target (I share your enthusiasm and cycnicism,-how's that for a dual activator). The fact is its here and needs to be addressed, why argue over utopian statements?

We also don't need birth control, just stop having sex except for procreation. How's that sound to you? Why did anyone waste time developing condoms. And after those were deveoloped what crazy money hungry pharma company developed the pill? Was that all wasted just because life-styles could just be modified?

Permalink to Comment

12. Soo Desu Ne? on September 25, 2009 1:08 PM writes...

Yeah, it's unmoderated. Thanks, Derek.

I want to do a rambling indictment of biotech in San Diego, but I have my own blog. This isn't the place.

I stepped on the psychiat and it hissed at me. That's some Harry guy.

I have been hammering away at nonscientists Roubini, Kunstler, and Orlov in the blogosphere but they've been winning, so you can't just characterize the arguments you can win. The inevitable tough arguments are global warming, and peak oil, but how exactly scientists can wind up with the wool pulled over their eyes is found by admitting a few things. Notice if CO2 is a pollutant, most of our concepts of toxicity are invalidated, and there's no second set of syntheses for these things.

I always wanted them to leave some petroleum for chemicals and not burn the last drop for fuel, didn't you?

The unavoidable thing is that you can't dispose of every anti-technology argument if in the near term we enter permanent energy scarcity.

I have just been reading about MPPP, by-product MPTP, active species MPP+, 1-methyl-4-phenylpyridinium. Now you got your PD model. Happy? SCI's spinal cord injuries. SChweet. I am not even saying. Some of the stuff's not intentional. What can I have to get high on, doc? There's too much pain and numbness in the world.

Permalink to Comment

13. In Vivo Veritas on September 25, 2009 3:44 PM writes...

Derek, it's the same or a very similar molecule in both papers. The chemist (DiMarchi) is also a principal at Marcadia Biotech, which Merck has a deal with.
The groups worked together and times the appers to not step on one another. Cool mechanism - I hope it works for them and for the obese population.

Permalink to Comment

14. Harry on September 25, 2009 3:44 PM writes...

@ No. 7

Hmmm- Logorrhea..check
Feelings of persecution...check
Feelings of grandeur...check
Finding patterns in unconnected
events...check.

Draw your own conclusions.

Permalink to Comment

15. Derek Lowe on September 25, 2009 4:14 PM writes...

SDN, I moderate things very lightly, deleting only vituperative stuff that adds nothing to the conversation. Only happens a couple of times a year.

That said, if you do indeed have your own blog, I wouldn't want to detain you.

Permalink to Comment

16. SteveM on September 25, 2009 4:39 PM writes...

Re: Harry and SDN

You know what Harry? BFD. At least the guy has panache...

Permalink to Comment

17. Morten G on September 25, 2009 6:40 PM writes...

@11. haywarmi

I hate the "obesity genes" brought up in mainstream media. There are some genes that protect from obesity despite leading a obesity-inducing lifestyle.
That said, it doesn't seem like changing from an obesity-inducing lifestyle to a healthy lifestyle leads to actual weight changes in most cases (yes it works for a few). So a drug approach is very useful. And that said!, I worry that people will have less motivation to lead healthy lives if there's an effective pharmacological option. Sedentary and junky ain't good for folks.

Permalink to Comment

18. Harry on September 25, 2009 7:09 PM writes...

Steve M.

Well if you say so...

Permalink to Comment

19. SteveM on September 25, 2009 8:11 PM writes...

Re: Harry

Right. Yawn...

Permalink to Comment

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