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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 6, 2011

Riding to the Rescue of Rhodanines

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Posted by Derek

There's a new paper coming to the defense of rhodanines, a class of compound that has been described as "polluting the scientific literature". Industrial drug discovery people tend to look down on them, but they show up a lot, for sure.

This new paper starts off sounding like a call to arms for rhodanine fans, but when you actually read it, I don't think that there's much grounds for disagreement. (That's a phenomenon that's worth writing about sometime by itself - the disconnects between title/abstract and actual body text that occur in the scientific literature). As I see it, the people with a low opinion of rhodanines are saying "Look out! These things hit in a lot of assays, and they're very hard to develop into drugs!". And this paper, when you read the whole thing, is saying something like "Don't throw away all the rhodanines yet! They hit a lot of things, but once in a while one of them can be developed into a drug!" The argument is between people who say that elephants are big and people who say that they have trunks.

The authors prepared a good-sized assortment of rhodanines and similar heterocycles (thiohydantoins, hydantoins, thiazolidinediones) and assayed them across several enzymes. Only the ones with double-bonded sulfur (rhodanines and thiohydantoins) showed a lot of cross-enzyme potency - that group has rather unusual electronic properties, which could be a lot of the story. Here's the conclusion, which is what makes me think that we're all talking about the same thing:

We therefore think that rhodanines and related scaffolds should not be regarded as problematic or promiscuous binders per se. However, it is important to note that the intermolecular interaction profile of these scaffolds makes them prone to bind to a large number of targets with weak or moderate affinity. It may be that the observed moderate affinities of rhodanines and related compounds, e.g. in screening campaigns, has been overinterpreted in the past, and that these compounds have too easily been put forward as lead compounds for further development. We suggest that particularly strong requirements, i.e. affinity in the lower nanomolar range and proven selectivity for the target, are applied in the further assessment of rhodanines and related compounds. A generalized "condemnation" of these chemotypes, however, appears inadequate and would deprive medicinal chemists from attractive building blocks that possess a remarkably high density of intermolecular interaction points.

That's it, right there: the tendency to bind off-target, as noted by these authors, is one of the main reasons that these compounds are regarded with suspicion in the drug industry. We know that we can't test for everything, so when you have one of these structures, you're always fearful of what else it can do once it gets into an animal (or a human). Those downstream factors - stability, pharmacokinetics, toxicity - aren't even addressed in this paper, which is all about screening hits. And that's another source of the bad reputation, for industry people: too many times, people who aren't so worried about those qualities have screening commercial compound collections, come up with rhodanines, and published them as potential drug leads, when (as this paper illustrates), you have to be careful even using them as tool compounds. Given a choice, we'd just rather work on something else. . .

Comments (7) + TrackBacks (0) | Category: Drug Assays | Drug Development | The Scientific Literature


1. Lester Freamon on December 6, 2011 10:23 AM writes...

Don't forget Medivation's MDV3100, a thiohydantoin that just crushed phase III trials:

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2. luysii on December 6, 2011 10:43 AM writes...

"the disconnects between title/abstract and actual body text that occur in the scientific literature". Particularly true for medical research describing a new (often a drug) therapy. The only attitude to take, was "How are they lying to me?" This became rather tedious year after year.

Here's a particularly horrible example from the past. The initial report was from the surgeons performing the study.

[ New England J. Med. vol. 328 pp. 221 - 227 '93 ] 444 men with asymptomatic carotid stenosis were randomized to 1300 mg aspirin/day and no surgery or 1300 mg aspirin a day and carotid endarterectomy. There was no difference in the rate of stroke and death over a 4 year period. The stenosis had to be over 50%. There was a decreased incidence of stroke by a 2/1 margin, and TIAs (transient ischemic attacks) were reduced (but no one dies of a TIA). The lack of difference in outcome despite the decrease in stroke was due to the high overall mortality, and the low yearly incidence of stroke even in the (high) medical group (of 2.5%).

As I read the fine print in the body of the article I noted that the operative mortality was 1.9%, the permanent stroke rate was 2.4% and the rate of associated stroke due to arteriography was .4%. Thus the total perioperative stroke and death rate was 4.7% ( nearly 1 in 20 ! ! ).

However, in the summary, the authors recommended operating on asymptomatic carotid artery narrowing greater than 50%.

Neurologists were up in arms. Here's one of the responses.

[ Neurol. vol. 43 pp. 2163 - 2164 '93 ] The reporting of the study was a disaster. They reported the results of surgery as a reduction in TIA and stroke. Actually there was no reduction in stroke, just TIA. 5 perioperative strokes occurred. For some insane reason they deleted the 4 perioperative deaths. Some patients had bilateral surgery, and the benefit was calculated on the basis of the operations (rather than the patients). "If a drug trial led to 4 deaths and 5 strokes within 30 days of its administration to slightly more than 200 asymptomatic individuals it would be either abandoned or studied scrupulously in controlled circumstances . . . "

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3. partial agonist on December 6, 2011 11:15 AM writes...

If I have a hitset from an HTS campaign (I get those regularly) and if those compounds are on it, I look at the other compounds first.

It's not because the rhodanines and their ilk are not "real" but because history teaches me that they are generally not optimizable for the necessary triple combination of potency, selectivity, and safety. I don't really see convincing evidence to the contrary.

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4. RM on December 6, 2011 12:49 PM writes...

The issue at hand, and the reason it isn't quite a big/trunks argument, is what happens when people get the news that rhodanines are problematic. There's the tendency to want to throw out rodanines completely - either by physically purging your screening library, or by immediately tossing any rodanine hits without further consideration.

I don't think the authors would have much issues with people who say "given their other issues, I'll look at the other compounds first (but I'll come back to the rhodanines later if nothing else pans out)". I think their beef is with people who are saying "I'm not going to look at rodanines at all, ever (even if nothing else looks promising.)" - The authors are stressing that problematic isn't worthless.

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5. pharmadude on December 6, 2011 7:09 PM writes...

From what I can tell, anything that med chemists say to be true is actually only true about half the time? Rhodanines are bad and only an idiot would think otherwise! That is, unless the rhodanine is in phase III or marketed, then it was a great idea to pursue it.

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6. Clueless on December 7, 2011 7:40 AM writes...

So I guess it's no big deal that rhodanine-bearing compounds have exhibited divergent activity depending upon whether the biological assays are done in the light (active) or in the dark (inactive)?

See: 10.1073/pnas.211178398
(PNAS October 9, 2001 vol. 98 no. 21 11879-11884)

The fact that the PNAS paper is not referenced in the current work is an incredible oversight by both the authors and the reviewers. Every result can be explained by invoking "photochemically enhanced binding"- and so the authors need to run the key control experiments (assay in the dark) in order to prove otherwise. If I'd been asked to review this manuscript, I would have rejected it unless the authors addressed the issues raised by the PNAS paper- what has happened to JMedChem's reviewing standards?

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7. Clueless on December 7, 2011 7:50 AM writes...

Apologies for 4 posts- the corante server kept timing out. Derek, is there any way to delete the duplicate entries?

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