KinasePro

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

Aventis in the Aurora arena

Posted by kinasepro on February 4, 2007

A combined US/FR effort results in a novel Aurora chemotype in EP1746097:

O=C1CCCC2=C1C(C3=CNN=C3N2)C(O4)=CC=C4SC5=NC6=CC=C(OC(F)F)C=C6N5

This scaffold is not entirely unknown, but it is new for the Auroras afaik. These were likely discovered as hits from an Ambinter or an aptly named Aurora screening library.

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7 Responses to “Aventis in the Aurora arena”

  1. weirdo said

    Why doesn’t that molecule spit out hydrogen faster than you can say “Jackie Robinson”?

  2. BeenThereBefore said

    let’s call it allylic strain …aromatization of the central ring would leave you with a scaffold flat as the Netherlands … forces the furane out of plane …not too much driving force to happen after all.

    Anyhow, I think that you still have a rather valid point by proposing oxidative metabolism to the aromatic system (via N-oxide formation). However, the central N being part of a vinylic amide, this might also not happen as quick as one would expect.

    Any opposing thoughts?

  3. weirdo said

    No way that furan is in plane to begin with . . . that hydride looks like it is just itching to find an oxidant of any sort. The vinylogous amide must be playing a role, I just don’t see it.

    But, hey, it’s just a patent application, wouldn’t shock me if they got the structure wrong. If there is no MS data, then all bets are off.

  4. kinasepro said

    Thats the way they, Aurora, and likely Ambinter draw the structures. Other then the a-strain argument, I don’t see why you couldn’t draw these as the tautamer with the double bond at the other bridgehead.

    Something peculiar at play here, but I don’t know what it is

  5. BeenThereBefore said

    In 3-Aminopyrazoles the tautomer with the NH in the 1-position is usually the one you end up with. From this perspective I am not too troubled with their structure (looks to me like the energetically favourable one). But I haven’t checked their experimental details …

    I guess that they also claim tautomers. The obvious question would be, if the other tautomer can still bind to a kinase hinge. Any thoughts on this, kinasepro?

  6. kinasepro said

    Hi BTB, My thoughts are that the pyrazole tautamer is as drawn, I think thats what you said, and I agree. That pyrazole likely sits just like the Nerviano stuff, and VX680. It’s the exotic 1,4 unsaturated part that has me scratching my head. I don’t know too much about this kind of stuff, I suppose I should :/ but I’m tempted to think that the other bridghead would allow the double bond to walk in to conjugation with the pyrazole.

    Pyrazole is only a weakly aromatic ring, and as I think you pointed out earlier the furan ring is out of plane and unable to participate. I wouldn’t argue too hard on any of this stuff though because its usually electron deficient N-H (aniline or amide) where the drawn vinyl-NH is.

    Beats me. Looks wierd though.

  7. weirdo said

    Dude, it’s spelled “weird”. The whole “i before e . . ” thing.

    I should know.

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