Posted by kinasepro on December 5, 2007
Alex Fernandez thinks he has a dehydron in action with Gleevec & c-Kit:
The interest of this goes way beyond this particular drug and this particular side effect. The idea is we could demonstrate for the first time that you can take a drug with side effects and re-engineer it to curb those side effects, Fernandez said in a telephone interview. (Reuters)
Adding a methyl group alpha to the the pyridine will make the activity of most kinases go away given a steric clash with the neighboring carbonyl. It’s interesting that the c-Kit activity stays behind, but the evidence given for the dehydron effect is through molecular dynamics and while as a rule I’ll try not to hold that against them, I don’t believe that the authors give a satisfactory answer as to why this new methyl group does not negate the compounds c-Kit activity through a simple steric interaction.
Nippon Shanyaku took the alternate tack of making the core pharmacophore more potent and made it hit other things… In the discovery of the ph1 compound NS-187 (Inno-406):