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24th February 2013 @ 10:51

As previously shown, a four common feature pharmacophore model (excluding the hydrophobic features for simplicity) can be used to map both the arylpyrrole (OSM-S-5) and near neighbour (NN) (OSM-S-35) series

Looking at some less active examples it can be seen that both aromatic features are required for potent activity as show by OSM-S-54.  Also, substituting the ester link for an amide (OSM-S-19) or a oxazole (OSM-S-62) kills activity. 

Not illustrated here but OSM-S-103 only showed weak activity suggesting that the ester linkage is essential for potent activity in the arylpyrrole series.

Wanted List

From the Wanted list the oxadiazole doesn’t look too promising based on the synthesised oxazoles.  The ether has potential but it does not appear to map to well and I’d predict it would have a similar activity to the carbonyl derivative OSM-S-103.

The sulphonamides look good and it’d definitely worth trying to make these.  In addition, the sulphonate also looks promising.  (At the time of writing this I’m not sure in the sulfonate is synthetically possible)

OSM-S-106

OSM-S-106 showed great potency but the mapped pose is flipped to as what was expected where the N3 would map onto the first acceptor feature.  This could either suggest the OSM-S-106 is acting in a different manner or it could mean that a meta-substituted sulfonamie is hitting a previously untouched pocket in the active site.


This theory could be easily tested by making a small number of derivatives (A-E).  Mapped are the phenyl substituted version on OSM-S-106 (A) and it’s morpholine analog (B)– this would potentially hit the second acceptor feature.  Finally the para-substituted version of OSM-S-106 is mapped (C), the sulfonamaide hits both the acceptor features but a the expense of the top aromatic feature.  This is worth making, again to validate the model and the poses calculated.  Compounds D and E would also help to confirm the binding of OSM-S-106.

 

 

In addition, the NN derivative with a meta-sulphonamide (F) could be a useful compound to make if the NN series is to be continued.  The sulphonamide group also greatly reduced the logP of the compound.

 

Attached Files
Slide 1.jpg
TCAMS.jpg
106.jpg
Slide 2_wanted.jpg
to make.jpg
to make_NN.png
to make1.png