Skip to main content


Another Funny-Looking Structure Comes Through

Here’s one that I certainly wouldn’t have thought about doing. This recent paper in ACS Medicinal Chemistry Letters describes changing the substituents off the core of a PAK1 inhibitor. Nothing too interesting about that, you’d think: the inhibitor itself is one of your standard-looking kinase inhibitor sausage strings of heteroaromatics. And that’s the problem, because those things can tend to have lousy properties when you dose them in vivo. Live by the Suzuki (and Buchwald-Hartwig) couplings, and die by them when you see the pharmacokinetics. So you often see polar stuff hanging off of these cores – it’s not there to help at the kinase binding site, but to drag everything along out of the gut, through the bloodstream, and to help escape the shredding machines in the liver. A classic example is Tarceva (erlotinib), which has those ethylene-glycol-based chains hanging off it mainly to keep it from being such a sun-baked brick after oral dosing. You can see the same sort of thing in Iressa (gefitinib), Caprelsa (vandetanib) and many others.

In this case, the molecule is FRAX1036, shown here. And that piperidine is the polar add-on, but it turned out to be more trouble than it was worth. Some of the medicinal chemists in the audience will be saying “hERG“, and they’re right. Piperidines and piperazines are great structures, and medicinal chemistry would be a lot poorer without them, but they can set off hERG activity, which can (in some cases) lead to heart rhythm problems, which can (in pretty much all cases) lead to your drug wiping out. And maybe taking you with it, depending on just how bad things got. hERG is one of those things that we didn’t used to understand very well, and arguably still don’t, but we understand just enough about it to make trouble for ourselves. Many older compounds made it onto the market with hERG activity in them, but no one is going to feel comfortable developing a compound with strong activity on that ion channel now, for fear of what might happen in the clinic. Even if it were to make it through, no one would feel comfortable sending it off for approval, for fear of what the FDA would make of it, because everyone would be worried about what might happen when the stuff hit the general population. Some hERG stuff can be dealt with via more predictive animal models (dogs wired for telemetry, with constant monitoring of heart rate), but a compound with lotsa hERG may not even get that far.

So the Genentech folks who were working on this structure knew from their previous work on this target that an amine pointing off in a different vector in the binding site (off the lactam nitrogen) could be beneficial. So they merged the two structures (along the way dropping one ring nitrogen, which didn’t seem to be needed). Adding this amine did indeed help the potency, by interacting with some polar side chains in the ribose-binding part of the ATP pocket, and several different things could be used to bring it down there – cyclohexyl, plain old n-butyl, what have you. But hERG activity was high, and cellular permeability was marginal, so something had to be done to make the overall compound less basic, but not so greasy that the PK properties got even worse. Putting that side-chain amine in position via a morpholine analog seemed to help a bit, but not enough. How about another oxygen? That’ll attenuate the basicity even more, while not greasing things up.

The solution is shown – compound G-5555 at right. And that’s a group that I wouldn’t have picked – even the paper describes it as “atypical”. Organic chemists in general may be raising their eyebrows a bit at it, because that two-oxygens-on-one-carbon group (an acetal, in this case) is known to be labile to acid conditions. Y’know, like in the stomach, which is where your drug is going to go when someone eats it. In this case, though, the dioxolane really performed well – in the same way that it reduces the basicity of the amine, the amine makes that acetal more stable. The team tried a number of acid conditions, trying to force the compound to degrade, but it held up. In rodents and monkeys, it showed low clearance and high bioavailability.

I’m going to have to readjust my thinking about these groups. I’ve seen them show up before, but I’ve generally made a face and figured that they were the work of desperate chemists. But any side chain that can turn around a compound this thoroughly deserves a more friendly welcome. Congratulations to whoever thought to put that group in there, because they probably got some of the same reactions that I would have given it, and we doubters would have been completely wrong. (But I still hold on to some of my deep-seated prejudices about other structures – there’s a limit, you know).

Update: corrected the structures, which I had left in a higher oxidation state due to not being fully awake.

14 comments on “Another Funny-Looking Structure Comes Through”

  1. Barry says:

    the beta-lactam was a “funny-looking substructure” in its day. Many chemists dismissed the possibility that it could exist. But the proof of a drug candidate is in the biological system, not on paper, blackboard or silico

  2. Rock says:

    I used to have a similar bias until Merck’s aprepitant was approved in 2003:

  3. Nick says:

    Atypical indeed. Nice post Derek. The structures are not quite right (lacking a C=C bond in the quinolinone ring).

  4. Useless Molecule says:

    Good Stuff.

  5. Me says:

    Reminds me of my days in macrolide chemistry. The glycoside bonds were very labile when you had a hydroxyl para- to the glycoside bond. You needed to go to pH 3 to get the sugar to come off. But when you stuck a primary amine there, you could reflux it in 6M HCl.

  6. PorkPieHat says:

    Brilliant, absolutely brilliant. Wish I’d thought of that. Could be broadly useful.
    And the glycoside chemist “Me” (at 10:41 am) is right….certainly precedent there.

  7. David Borhani says:

    Topamax (topiramate). ~70% is absorbed and then excreted via urine unchanged.

  8. AQR says:

    The first step in the hydrolysis of the acetal is protonation of one of the acetal oxygens. Under the acidic conditions of the stomach, the amine is already protonated. That makes the acetal oxygens less basic because it requires the formation of a dication.

  9. Sean says:

    I think the drug industry has to change, more and more HTS is used to search for 1 type of activity so it’s possible that the same compounds may be tested MANY times. I always set the bar at Paul Janssen who would take a scaffold and see what it could be made to do. I mean, for pethidine came haloperidol, phenoperidine & diphenoxylate and another half-dozen others. neuroleptic, anesthetic. antidiarrheal from 1 scaffold.
    He brought at least 1 drug new drug to market every year for about 30 years.

    There are some GREAT chemists (we all have out lists) but of medicinal chamists, only Meneer Janssen.

  10. Bruce Maryanoff says:

    As the inventor of topiramate, which contains two ketal groups, I have to say how much flack I caught in trying to champion clinical development of the compound. Bunch of naysayers out there, with inherent chemical prejudices. We verified its stability to simulated gastric fluid and the rest is history: a billion-dollar drug!

  11. hopeless says:

    too many clueless chemistry managers in medchem department

    not hard to come up this structure from a chemist who noticed it’s very hard to hydrolyze an acetal group when there is a basic amine nearby

  12. anonymous says:

    talking of precedents, a quick substructure search turns up the exact same 5-amino-1,3-dioxane in somatostatin agonists published 16 years ago:

  13. Sean says:

    Bruce Maryanoff – a perfect example (and well done BTW!) of people who graduated in chemistry and then got jobs as marketing or management of a medicinal chemistry company. They get years between graduating and going into a lab & remember only parts of their degree (use it or lose it). Disgusting that the Medicinal Chemist is no longer the end of the line. I damn the DSM IV & now the DSM V for keeping a scaler out of the tests for an illness. That way, if the patient ticks more than 4 boxes and voila, a diagnosis. You can guess what I was doing 25+ years ago!

  14. Henry Rzepa says:

    The stereochemistry of the amino group is crucial here. The stereochemistry reported aligns the N-C bond with the acetal O-C, thus reducing the basicity of the oxygen lone pairs and lowering its ability to start the hydrolysis by protonation. The other epimer is predicted to hydrolyse faster. For details, see

Comments are closed.