KinasePro

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

The Vertex J Med Chem

Posted by kinasepro on February 18, 2007

TM brought it up… So here’s my two cents on the latest Vertex J Med Chem.

TM thinks the pyrrol – pyrazoles are ubiquitous, and Vertex says: ‘Kinase activity of pyrazolylpyrroles has been reported previously.16-18′

16:Vertex; WO/2001/057022
17:Vertex; WO/2003/011854
18:Vertex; WO/2003/011855

But refs 16-18 are the apps which cover this series and that’s about it for the 3 pyrroles. The 2-pyrrole substructure can be seen all over the place from things like the DNA/Roche aurora indoles, to chk1, to plenty of others. A subtle difference, but all the difference given how these hit the ERK hinge.

Anyhow, in going after the ERK gatekeeper with the pyrrole, it is surprising to find JNK3 activity since the JNK gatekeeper is methionine rather then glutamine. Interestingly the ligand adopts a flipped conformation in JNK3 more reminiscent of what you’d expect from the pyrrol-2-yl-pyrazole, like indoles, benzimidazoles and such.

smiles_O=C(NC(CO)C1=CC=C(F)C(Cl)=C1)C2=CC(C3=C(C4=CC=CC(Cl)=C4)C=NN3)=CN2

The way the paper is worded it seems as though the selectivity was worked out in advance of the structures being obtained. Heh.  If nothing else, the PDB’s give a good example of a pyrrole tightly hydrogen bound to GLN. 2OJG, 2OJI, 2OJJ, 2OK1,

Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

 
%d bloggers like this: