yeh, its the pyrrolidine version of Sutent & its the phosphate salt
This entry was posted on June 3, 2009 at 10:33 pm and is filed under Approved, Pfizer.
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I would not recommend anyone Palladia for the unapproved human use. Sutent has already too long half-life of the active metabolites and it has a non-linear dose-response curve, and the tox profile is not very favorable (the safe dose is quite narrow, with QTc prolongation and organ accumulation-related toxicities seen in animal studies – adrenal necrosis and heart damage, among others problems) Sutent recommended therapy course has a treatment-free ‘holiday’ (like with conventional chemo) so that the patient can recover. Palladia is an analog that has even longer half-life in vivo, and most likely it is not any safer. The side-chain has actually a huge effect on the PK and toxicity profile. The improved safety profile clinical backup analog for Sutent was SU14813; it has a less basic 3-morpholino-2-hydroxy-1-propyl sidechain (and needs to be dosed somewhat higher and bi-daily).
That is very interesting… I kind of assumed that the pyrrolidine vs. diethylamine was merely for novelty (patentability) because the side chain is on the solvent exposed side. But now that I think about it, the side chain is also what tends to get metabolically chewed up first.
I don’t think you will find the history because the SUGEN company is long gone and the detailed account of the history was not published AFAIK. This work was done in a very small chemistry group (that did not even have its own NMR at the time) and they had to choose some simple side-chain. So they did dimethylamino, diethylamino, morpholino, pyrrolidino, piperazino etc and they looked at the potency vs toxicity and the half-life in animals.