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

Got Spiro?

Posted by kinasepro on January 14, 2007

US20070010539 is a GSK3-beta application. This series goes back to ’01, and the pictured spiro compound hit the streets in ’05. Publications on these? Other then an expert opinion (which my library doesn’t carry) and them naming SAR502250 a preclinical development candidate (also in ‘05), I haven’t seen anything. While I don’t relish posting old news, the novel spiro architecture was enough to make KP lift an eyebrow.


Only they know if these spiro compounds are the lead structures, but it looks like a well developed chemical series with an interesting story to be told, and since they’re not talking… I will.

Making libraries around known kinase inhibitors is the gold standard in early discovery. A modicum of novelty together with a vague idea of the structural biology and as long as you’ve got a screen – you’ve got a program. One might be surprised to learn the kind of mileagle you can get with a few creative isosteric replacements, and the ability to hang diverse functional groups here and there.

Take LY294002 for instance. A mere 1.4 µM inhibitor against Pi3K, but its a teeny little thing, and ripe for some analogging. A few libraries, some creative chemistry, and we’ve got a potent series against GSK3B.

Multiple applications in ’01 with some data suggesting they can make very potent compounds with a fair amount of diversity in the lower left region. Interestingly the pyrimidine and pyridine are used interchangeably without impact on GSK3 activity.

What appear to be the second generation applications are primarily a survey of that lower left region. The chiral morpholines are made racemic and then separated. As you might expect there’s a good deal of overlap and the three examples shown hit some of the hilites.

Third generation sees an entrance into chiral piperazine linkers, in addition to the more exotic spiro fused style compounds – both pyrollidine, and piperidines. This outside observer also thinks that there must be something special with the chiral phenethyl alcohol.

The most developed sub-series are clearly the chiral morhpholines and if pressed I’d guess the development candidate was burried in there somewhere. The spiro compounds are a fascinating modification, but my gut feeling is that they are backups.

No selectivity is talked about in any of these applications, but the homology of GSK with kinases like CDK5 suggest to me that selectivity is likely an issue they have had to wade through particularly for a chronic indication like alzheimers. They also have the added complication of the triple B.

There are a few GSK3 crystal structures in the PDB, but these compounds make more sense when you look at them together with LY294002 and even some of the CDK5 structures give a good understanding of what the spiro amines are likely doing.

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