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


Posted by kinasepro on June 9, 2009

In Ph2 for COPD & it’s an atropisomer…(biochem)


Who wants to guess if its R or S

Process App: 20080177077
Backup: 20080269264

6 Responses to “PH-797804”

  1. milkshake said

    this is a fairly old and very potent compound that Pfizer inherited from Pharmacia. (The follow-on pyrimidinone analogs are even more potent).

    It would be very interesting to see the long-term effects in the COPD patients taking a p38 inhibitor with regards to 1) liver function 2) atherosclerosis/fragile plaques and MI

  2. kinasepro said

    You can always tell an insecure modeler when they feel the need to point out how perfectly predicted everything was while ignoring the important bits. It’s an entertaining paper in a shark-jumping sort of way.

    All I’m saying is, everyone seems to have a VX-702 / VX-745 styled compound these days. It’s the last best hope of finding a marketable p38 ‘nib. The novelty of this one is the halogen bond to H107, and the paper completely misses it… & To ignore 1M7Q but include 1R39 (APO) & 1CM8 (AMP)?

  3. Philip said

    It’s S as drawn.

  4. milkshake said

    the link you gave unfortunately does not work. The halogen certainly does something important – without it the compounds are at least two orders of magnitude less potent, if I remember correctly

  5. petros said

    From the abstract this would appear to be remarkably selective for p38 alpha. If that is the case it could eliminate the toxicity/side effects issues that have plagued p38 inhibitors since SB first described them as CSAIDs. It would also distinguish PH-797804 from the majority of p38 inhibitors, which have shown little discrimination betwen p38 alpha and p38 beta. But is that distinction clinically valuable or not?

    • milkshake said

      No, the old Scios compounds with indole (and our oxalic anilide knock-offs) had over 10-fold selectivity to alpha vs beta.

      If I remember correctly this particular Pharmacia compound had a pretty fast liver microsomal oxidative metabolism – so this could be used in inhaler(and the fast metabolism would be a bonus, to reduce the systemic exposure) but apparently they are going ahead with the oral dosing.

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