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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: Twitter: Dereklowe

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« March of the Ugly Tool Compounds | Main | Improving Half-Life »

October 23, 2012

Huge But Effective

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Posted by Derek

Of the physical properties that make up the "Rule of Five" (and similar schemes), the one that I think is easiest to breach is molecular weight. I'm not saying that it's a good idea to breeze past 500 daltons with a song on your lips - you should always realize that you're probably asking for trouble up there. But trouble seems to follow a bit less often than it does with, say, a high logP. For a high-value target, I think it's certainly worth pursuing if that's really where you have to go.

Here's a whopper of a molecule, for example, an inhibitor of PTP-MEG2 (also known as PTPN9). That's an unusual phosphatase involved in hepatic insulin signaling, and it's already been shown that knocking it down seems to be beneficial in diabetic rodent models. But, like another longtime diabetes target in this space (PTP1B), it's not easy to get a decent inhibitor. Phosphatases are tricky. Their active sites are very polar (as you'd imagine, having to work with phosphate anions all day), and there aren't all that many phosphatase subtypes as you'd expect, given the amount of such work there is to do. That leads to worries about selectivity, even should you find a molecule that seems to work.
So if you can't find a decent inhibitor, how about an indecent one? That's the first reaction on seeing the structure at left. You can certainly see its resin-bound peptidomimetic library roots. I only wish the authors had found a way to incorporate a chlorine atom somewhere; it would have been one of the rare compounds that runs the table on the halogens. As it is, this floating island weighs 1084, well beyond what anyone could consider reasonable for a drug candidate.

It's selective, naturally. Something this size is making so many interactions that its chances of fitting in a lot of different places is quite small. (There's a crystal structure, which doesn't appear to be showing up in the PDB as yet). It's got a Ki of 34 nanomolar against its target, and about 600 for PTP-TC and PTP1B. All the other protein tyrosine phosphatases are dead, and I'd be very surprised if it hits something from another class. But selectivity isn't the hurdle for these leviathans - it's pharmacokinetics. And here we have a surprise.

First off, the compound shows good activity in mouse heptatocytes, and in other insulin-sensitive cell lines. That's quite interesting, since PTP-MEG2 is surely intracellular - so what part of the cell membrane is letting Godzilla through the turnstiles? The authors moved on to i.p. injection in mice, and found that at at 20 mpk level the compound hit a Cmax of 4.5 micromolar (pretty respectable, considering that molecular weight), and had a half-life of 1.8 hours. That's short, but not as short as one might have feared. Multiday treatment of mice showed just the sorts of on-target effects that one might have predicted: inhibition of hepatic gluconeogenesis, enhanced glucose clearance and insulin sensitivity. That's just the sort of profile you'd want for a Type II diabetes drug, and with a bit of work on the half-life, you might have one here as an injectable. I don't hold out much hope for oral activity with a molecule like this, but it's impressive that it gets this far, and it provides some real proof-of-concept for PTP-MEG2 as a drug target.

So in case anyone's wondering whether I can say anything kind about tool compounds, or about academic drug discovery (this paper's from Indiana U), well, here's your evidence. I don't know whether the authors were brave or just foolhardy to consider these structures, but they've latched onto something worthwhile.

Comments (21) + TrackBacks (0) | Category: Diabetes and Obesity


1. NMR jock on October 23, 2012 8:10 AM writes...

If someone comes around asking for analytical characterization on this behemoth, I've already called "Not it!"...

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2. Pete on October 23, 2012 8:20 AM writes...

I admit that it's a big ugly brute but, given the state of Drug Discovery, we do need to be asking how much we really know about drug-likeness? Just how strong are the trends upon which our opinions of drug-likeness are based?

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3. Old Lab Rat on October 23, 2012 8:27 AM writes...

Wonder what the plasma protein binding is? I'm also curious how long the iodine stays attached. Still, as Derek mentioned, it's one of the better tool compounds to come down the pike.

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4. Pharmacologyrules on October 23, 2012 8:38 AM writes...

A t1/2 = 1.8 hours in a mouse is not too bad--but I would feel more comfortable stating a t1/2 after i.v. administration.

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5. nitrosonium on October 23, 2012 8:50 AM writes...

as an organic chemist slowly learning about med chem and discovery/development issues i have a question about increasing the t1/2 as derek mentioned. how does one go about improving such things? structural changes? formulation??

and would there be any value/use in screening smaller fragments or intermediates of this? could you get better activity or pk way before you get to 1085 MW?? i did not read the paper yet

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6. Tim McDaniel on October 23, 2012 8:51 AM writes...

Well, technically, to run the table on the halogens you'd need astatine too, but there's a minor problem with that ...

I'm not a chemist. Can I assume the 6 nitrogen atoms are not a problem because they aren't adjacent and they aren't a high percentage of the total?

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7. Curious Wavefunction on October 23, 2012 8:59 AM writes...

What matters is not whether it's ugly but whether it's the right kind of ugly, like cyclosporin A.

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8. Pharmacologyrules on October 23, 2012 9:27 AM writes...

I have had 5 beers since reading this and the compound looks much less ugly now than it di before the 1st beer.

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9. milkshake on October 23, 2012 10:54 AM writes...

2 hour halftime in mice is not bad. And with some pro-drug on the difluoromethylene phosphonate it could even get even orally available. This looks quite reasonable, for a peptide but if it is to be used in gram dose I would just make sure that it does not have any unpleasant diaminopropionic acid metabolites, Dap modified on beta amino is a potential source of problems, there are several nasty plant toxins based on Dap

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10. Chemjobber on October 23, 2012 11:32 AM writes...

8: LOL.

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11. barry on October 23, 2012 12:14 PM writes...

if I achieved 2hr half-life in a mouse with oral dosing, I'd worry that it was too long, not too short. But this thing isn't going oral. Let's see that x-ray co-crystal structure and maybe we can design a proper SMALL molecule inhibitor, with oral availability and a better chance of passing cell membranes.

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12. David Formerly Known as a Chemist on October 23, 2012 2:22 PM writes...

@11...problem with designing small molecule inhibitors of PTPs is the high homology between enzymes and the fact that the active sites are very shallow, near the surface of the protein. That makes it very difficult to design selective inhibitors of PTPs that are low molecular weight. Adding all the functionality (like you see in this structure) is what allows you to get selectivity. If I recall correctly, PTP1B (once a very hot target) quickly fell out of favor because it was damn near impossible to separate inhibition of PTP1B from TC-PTP.

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13. Hap on October 23, 2012 2:27 PM writes...

The betaN-oxalyl-DAP is apparently a neurotoxin of note (see this reference) - it's proposed to be the cause of neolathyrism. I guess whether you'd worry would depend on from which end the compound unravels.

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14. gippgig on October 23, 2012 2:52 PM writes...

#6: you'd also need element 117.
That pattern of nitrogens is a peptide, the same structure found in proteins.

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15. anonymous on October 23, 2012 6:31 PM writes...

Ah... the miracle of (hetero)aromatic ring addition (up to a point, that is!)

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16. milkshake on October 23, 2012 7:24 PM writes...

@13 there is also beta-N-methyl-Dap aka BMAA that is strongly suspected in causing ALS + Parkinsonism in people that eat BMAA-contaminated food and Mimosine, a cell arresting toxin that blocks DNA replication

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17. Vader on October 24, 2012 10:08 AM writes...

No offense to all the hard work that went into this, but I think I'll stick with metformin for now.

No, really. It's not enough that the drug works for diabetics; it also has to offer some advantage over existing drugs, which include some pretty good ones. That's a pretty high barrier.

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18. barry on October 24, 2012 11:13 AM writes...

if this behemoth can achieve enough pharmacodynamic effect to validate or invalidate the target, it will have been worthwhile. It seems a poor bet for drug development.
Parke-Davis showed that--sometimes--you can replace an aryl iodide with a terminal alkyne. Depending on what that phenol is doing (H-bond donor? H-bond acceptor? both??) there are known isosteres that--sometimes--work. But that difluorophonsphonic acid emerged from a lot of work on tyrosine phosphates. That's a very hard motif to fake.

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19. I_can_beat_that on October 26, 2012 12:17 PM writes...

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20. ddddddd on October 26, 2012 6:27 PM writes...

I used to work in precious metal protein inhibitors, and I always thought that MW was a silly metric for PKs. After all, a platinum atom weighs about 200, but if anything, it makes your compound *more* water soluble.

Can anyone answer me this: Why don't we just deal in No. of heavy atoms (i.e. non-H atoms?)

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21. Timo Niedermeyer on November 10, 2012 2:44 AM writes...

I tried to comment on this post, but I think that my comment did not make it past the spam filters... So I have extended my comment and put it on my own newly established blog.

If you are interested, feel free to have a look at

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