Intramolecular hydrogen bond between amide NH and piperazine? CSD may shed light. Form the ring with real (as opposed to hydrogen) bonds and a patent bust could be in the making. Are those structural types encountered in Aurora kinase inhibitors? On another note TTP-607 looks like it would pack well into a lattice. Maybe too well. Is the piperazine somwhere that some of that symmetry could get broken?
Aminobenzimidazoles are intereting beasts. I seem to recall that the pKa of the parent is about 7.5 so it can look a bit like the business end of arginine. Putting a phenyl (especially with the electron-withdrawing CF3) on the nitrogen will drop this pKa so in TTP-607 this group will be a good urea mimic. It is probable that in the beta-secretase inhibitors the aminobenzimidazole is protonated since proteases often sit in low pH compartments.
It’s probably a good time to mention that I really like the kinasepro site. I’m guessing that the relevant pharma companies would prefer that folk didn’t comment on their structures (especially with respect to patent busting) which is an excellent reason to comment. You keep blogging and I’ll keep commenting!
Just a side note – to my knowledge, TransTech has not released the structure of their lead compound: TTP-607. The above pictured structure has been dosed IP in several Xeno’s (described in WO/2007/95124) suggesting that at some time they considered it worthy enough to perform advanced in vivo studies on it, but thats about all that can be said.
It is conceivable that their lead structures could be from some another series, but you can be the judge on how likely it is that a small group spread over multiple projects might have the time to get involved in building multiple series from the ground up.
The response of cancer cell to a drug action thru whater resistance mechanism,
tranporter, mutation, turning on other pathway….., is a postive sign for drug’s efficacy. Noting that no anti-cancer drug has yet provided a cure therapy, resistance is a biomarker offering a strong support for a compound as a new drug candidate.
I’m not sure what JJ means by resistance = biomarker… I haven’t heard this. I think it might be hard however to gauge how ‘ good ‘ a series is based on just a look at the structures… There are some IP dosed xeno’s descdibed in the application though.
Once again, generally speaking, whaterver resistant response of cancer cell, vs mutation (happened more frequently in the clinic) or trasporter pumping, is a positive sign to look at the action of a compound. In other words, acquired resistant mutants (protein) or the drug molecules (or metabolites) pumped out of the cance cell are a ‘biomarker’ for the cancer cell’s response.
Rely mostly on what I have experienced. Now I’m tempted to write 1, 2, 3…as seen in piles of old papers, but would fall into the claws of the surrounding kinase-wolves :~~). I’m gonna run a consulting firm. Feel free to drop me a line in my email box then.