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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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December 4, 2008

Curse Of the Lost Compounds

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Posted by Derek

There are some groups of compounds that seem to have a curse on them. They show up in drug screening, they have activity that’s often too good to ignore, but hardly anyone can manage to turn one of them into a drug.

Trifluoromethyl ketones are one example of this. They’re classic inhibitors of proteases, especially serine proteases, and of other enzymes that depend on a serine in their active site. That’s because that ketone really isn’t much of a ketone – the fluorines make the carbon rather unhappy when it’s in that state, electron-poor and ready to pick up a nucleophile and go tetrahedral again. Trifluoromethyl ketones are generally seen in their hydrated state, unless you take care to dry them out, and they’ll work an active-site serine OH into their scheme as well. So you end up with a covalent inhibitor, but a reversible one – the activity comes on slowly, and the compound comes off slowly, too. That trick can work with cysteine nucleophiles, and the hydrate form is also known to coordinate with active-site zinc atoms – so it’s no surprise that the enzyme inhibition literature on these things is mighty extensive: proteases, lipases, esterases, deacetylases, the list goes on for a while.

But although several of these have gone into the clinic over the years, I can’t think of one that’s make it all the way to the market (I’d be glad to hear of any that I’ve overlooked). The best guess is that this isn’t the fault of the functional group, but of the targets it’s been applied to. Some of these enzymes just haven’t panned out, so perhaps the trifluoromethyl ketone awaits its day in the sun.

Another group of this sort is the hydroxamic acid. Its strength is its coordination to zinc atoms, so you see it all over the place in the metallaloprotease literature, and in other zinc-y fields like histone deacetylases. And in vitro, it hardly has a peer. I’ve seen list after list in the literature comparing various zinc-binding head groups, and likely as not, the hydroxamic acid sets the standard every time.

But the reason you see those lists is that people are trying to find something that’ll work other than a hydroxamic acid. There are numerous complaints, ranging from “hydroxylamine is explosive on large scale, you know” and “they’re a pain to make reproducibly” through “they have ugly PK in the animal models” all the way up to “they’re toxic” and “how many of them have ever made it through the clinic?”. How much merit each of these have can be debated, but all together they make an unpleasant picture.

In this case, though, I do know of one that’s made it - SAHA (Zolinza, vorinostat). That one came out of a long-term academic project involving Paul Marks at Sloan-Kettering and Ron Breslow's lab at Columbia, and is one of the not-so-numerous examples of drugs that have made it from the university to the marketplace. Merck signed up to do the clinical and regulatory lifting on this one, and it's now marketed for cutaneous T-cell lymphoma.

So it is possible to get a hydroxamic acid through. "Well, yeah," say the voices, "for cancer, sure. Home of the world's only boronic acid-containing drug. Home, if you really want to get down to it, of nitrogen mustards and God knows what else. Cancer." And it's true that the standards are a bit more relaxed there. I wouldn't necessarily want to give someone a hydoxamic acid every day for the rest of their life, true - the things coordinate iron, for one thing, which isn't always good. But there are other fields where short-term therapy makes sense, and we probably haven't seen the last of this functional group, either.

Comments (30) + TrackBacks (0) | Category: Cancer | Drug Development | Drug Industry History


1. Jose on December 4, 2008 10:00 AM writes...

C&EN cover story, "Industry Reforms to drive innovation." Shouldn't that read "Industry cuts, draws and quarters staff to drive bottom line?" The ACS is sounding more and more like the ACC everyday.

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2. Anonymous on December 4, 2008 10:28 AM writes...

Dear Derek,

Nice topic. How do you see the presence of "P" in drug candidates? Cheers

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3. Hap on December 4, 2008 11:07 AM writes...

How exactly does laying people off and sending jobs to smaller companies and overseas constitute "innovation"? Companies have been doing that for a long time. If companies had ways to find better drug candidates and get them to market more quickly (without getting sued to death or having safety issues), they wouldn't have had to lay off people or outsource in the first place, since they would be able to better use the employees that they have and make more money from them than other companies could. (They might also have their pick of the people laid off from other companies as well.) They might outsource anyway, but that would depend on differences in employee capabilities and cost.

The other problem is the inevitable "we don't have enough chemists" commentary. Either recruiting people who have no better choices or encouraging people with promises of a better tomorrow is a rational response to decreased job security and pay and increasing educational requirements. Um, OK?

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4. SRC on December 4, 2008 3:41 PM writes...

C&EN is like People for the pocket protector set (i.e., guys like us). Full of feel good fluff and utter nonsense.

The "we don't have enough chemists" bleat particularly irritates me. American students know perfectly well that a career in science entails a lot of hard work for minimal reward, lousy job security, and a career reporting to someone who ultimately reports to someone with a bachelor's degree in marketing.

That's why they generally avoid it like the plague. Only the truly hardcore committed and/or not too bright types (us again!) ignore that reality and go into it anyway.

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5. Hap on December 4, 2008 4:13 PM writes...

Are trifluoromethyl ketones likely to stick (at least temporarily) to lots of things, making their pharmacokinetics not so good? I don't figure the fluorines are coming off, but if the compound is smeared all over, dosing is likely to suck.

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6. milkshake on December 4, 2008 9:00 PM writes...

One ugly but potency-improving group is benzamidine. Hard to replace, hard to pro-drug. Free amidine in the drug is bad for oral availability.

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7. Dr. Bloomquist on December 5, 2008 4:36 AM writes...

Adrafinil comes to my mind, although it does not currently have FDA approval.

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8. Harry on December 5, 2008 8:36 AM writes...

C&E News has been taken over by the PC/Environmentalist/Chemical Hysteric set.

There's not a single issue that doesn't hyperventilate over some largely theoretical risk and/or Global Warming. I've largely quit doing anything but skimming through it.

Some of the technology articles remain interesting, but the editorial slant is pretty blatant.

My $0.02, YMMV.

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9. milkshake on December 5, 2008 3:18 PM writes...

Adrafinil is a good point - it is an accidental prodrug that rapidly transforms into modafinil in vivo. Maybe thats why the parent hydroxamic acid does not cause much grief.

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10. A nonny mouse on December 15, 2008 6:53 AM writes...

Having worked on hydroxamic acids for many years, and back doing so again, it has to be said that the major problem with the "straight" hydroxamic acids (complex acid, simple hydroxylamine) it that they are extremely metabolically unstable; SAHA for instance has a half-life of 1h and bioavailability of 10%. A hydroxamic acid compound, tepoxalin, has been in use for arthritic dogs for several years, but in human trials caused liver problems due to the large doses to get a decent blood level.

As stated above, hydroxamic acids can be used as pro-drugs such as in ibuproxam and bufexamate.

The option with many hydroxamic acids is to make a "reverse" version (complex hydroxylamine, simple acid). Several companies have been looking at these molecules for many years as anti-bacterial agents which have been on trial at very high doses (3g single, 2g/day 14 days). The problem here, was not the compounds, but rapid bacterial resistance. Novartis continues to work in this field.

Other reversed hydroxamic acids in development include anti-malarial compounds with the N-formyl or N-acetyl hydroxamic acids. This switch, however, does not appear to work with HDAC type molecules.

My own efforts in this field some 20 years ago resulted in "reversed" hydroxamic acids with a half-life of >15h at 1mg/kg in humans. The project was dropped, however, after a take-over (as were most of our projects!).

As with your comments above, I have had people state that they are toxic, but with little real evidence (the person saying this also stated that changing to a different group caused the same toxic effect).

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