Kinase Chemistry – Just a year and a half behind the times.

Astex: An Oral Candidate for CDK2

Posted by kinasepro on November 23, 2007

Astex’s fragment based discovery effort yielded an oral candidate back in ’05, and now with WO/2007/129066 & WO/2007/129062 the world can have a look. It’s probably AT-9311 even though I could’a swore I heard’m say that their Novartis’ partnered material was of a different series then AT-7519. Perhaps its 7519 I have wrong…


0.22 uM GSK3b
Mouse: 40-50%F (DMSO/Water/PEG 1/2/7)

12 Responses to “Astex: An Oral Candidate for CDK2”

  1. Does the oral candidate also cause increased diuretic problems? (Although admittedly not too much otherwise it wouldn’t be lucrative). This seems to be a good control experiment for determining that sulfonamide groups can lead to increased diuresis.

  2. milkshake said

    This sulfonamide should not have an carbonic anhydrase activity. ArSO2NH2 is more problematic, its the other complcation is a sporadic alergy to sulfonamides.

    The generally bad thing about sulfonamides is that they are pretty polar and putting them into a molecule often ruins the cell potency/oral availability. And replacing them with something similar is not easy.

  3. weirdo said

    The great thing about generalizations in medicinal chemistry is that they are generally not very general.

    I love sulfonamides. Generally great for bioavailability and generally fine for cellular potency, in my experience. And generally easy to replace, in my experience.

    Must be some reason so many odd sulfonyl chlorides are commercially available from specialty suppliers.

    To each his own.

  4. I think the carbonic anydrase activity of sulphonamides is due to interaction with zinc cation and they need to loose a proton to do that. Milkshake will correct me if I’ve got that wrong. Tertiary sulphonamides are probably no more polar than analogous sulphones. Anyone seen an Ames result for anything looking like the hydrolysis product of the benzamide?

  5. milkshake said

    Well I was on 3 separate projects with my last 3 employers where we had to deal with a problem how to replace sulfonamide with something else. In the first case the replacement was a sulfone which had better cell potency but still had huge problem with metabolism + solubility and exploring the ways how to get around it ended up with abandoning the molecule and working on unrelated series.

    The second project had problem with making compounds orally available, the sulfone was replaced with urea or amide and the compound still had a lousy absorption. The problem with oral absorption did not get solved, the project got shelved and people fired shortly after.

    The third project had very potent sulfonamide compounds that did not work in cell, all attempts at finding a substitute failed. Eventually the parent compound without the sulfone was improved in other places (even though it required stepping back to <20 fold less potent series). Now t is without sulfone it works in cell now and has a good PK.

    The problem with sulfone is that it is fare more polar piece than just amide so if you put it in your molecule and if your target needs to have a good potency in cell (unlike antibiotics, receptors, etc) and especially if you want a brain penetration it means that you cannot afford to put too many other polar groups into the molecule. So if you have started with already a large polar molecule and you add sulfone, you can get gain in biochemical potency or selectivity but make the compound undruggable.

    My “Lipinski count” is 1 sulfonamide = 2 amides

  6. kinasepro said

    Re: cellular potency. I might propose that the sulfonamide NH is more prone to bind to the BSA present in cellular assays, and other ‘plasma proteins’ like albumin in vivo. I prefer to shy away from functional group taboos and would rather let the data be the data. Heck, even Pfizer appears to have a ph1 kinase inhibiting sulfonamide in trials. Of note, it – like SU-11274 are the N-Me.

  7. Hap said

    Sulfonamides shouldn’t inhibit CA unless they have at least one NH – their active site inhibition of CA depends on mimicking water in the active site by being deprotonated and binding to Zn (Zn-OH2 has a pKa of about 7, about what the sulfonamide NH pKa is). The active site is conical, so you probably can’t put two big substituents on the N without compromising CA binding (though I am not as sure about that). (I did a little bit of related research in grad school).

  8. “I prefer to shy away from functional group taboos”

    Well said. Sometimes we all have too much of a knee-jerk reaction towards fn groups. We need to lay our “weird-functional-group” antenna a little low sometimes.

  9. Petros said

    I’ve checked back on what I’ve heard said, or been reported, by Astex on these. It seems that at the 2006 Spring ACS they stated that AT-9311 was was derivative or AT-7519. So both structures may be right.

  10. If I were to be setting rules for sulphonamides, I’d be looking at whether they were tertiary, primary/secondary and/or anionic. I don’t think of tertiary sulphonamides as especially spiteful. Anionic sulphonamides can be troublesome. The sulphonamide NH is likely to be a stronger hydrogen bond donor than its amide equivalent.

  11. Petros said

    The structures are almost certainly right. A presentation yesterday (at Hatfield) described the M wt of the two compounds as 382 and 460 Da, which is consistent

    That of the Akt inhibitor AT-13148 is only 314 Da.

  12. Ed said

    If there was any doubt, I guess that would confirm that this their Akt candidate

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