This entry was posted on October 27, 2007 at 2:48 pm and is filed under biotech.
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Interesting to see that astrazeneca flag up ‘certain phenols’ as undesirable functionalities. Presumably this has something to do with the fact they actually sell a phenol as an intravenous anaesthetic. I believe anilines feature as histone deacetylase inhibitors.
glucoronidation being a clearance mechanism means your phenol will be cleared rapidly… The one drawn has the added complication that it’s a bis-phenol clearing a path to the quinone which can be a reactive intermediate.
One notorious functional group missing from the figure that will cause toxicologists (and learned med chemists) to run screaming from the room is a thiocarbonyl. Doesn’t matter whether it is a thioketone, thiourea, thioamide, etc. I’ve seen a couple from the literature go into the clinic, but the evidence preclinically and clinically is overwhelming against them.
Thiocarbonyl compounds are potent metal chelators and have typically poor PK. But for cancer therapy, almost anything goes.
With Sutent, there was worrisome QTc prolongation and other organ tox (adrenal necrosis) in animals from what I heard, together with non-linear PK and tendency for the drug to accumulate. And you see, it sells well. So much that Pfizer shelved the follow-on candidate with improved tox/PK properties.
I don’t know, I was just a chemist making analogs. At the time management was very nervous because if the compound was to be dropped in the clinic, it would have been the third failed clinical candidate in the row. (The first compound failed due to poor solubility, the second one for high plasma protein binding – easy problems to spot but they were not appreciated until late in the trials – a very expensive mistake)
The Sutent regiment calls for a week-long ‘holiday’ after couple weeks of therapy – I suppose this is because of some accumulation and relatively narrow safety margin but I don’t realy know. Sutent has huge volume of distribution and is quite persistant and the major equipotent (and probably more toxic) desethyl metabolite has even substantially longer clearance time.
One way you can tell accumulation is happening is the patient skin turns “bronze”… the compound is intensely yellow-orange
The diagram is not an AZ creation, it’s just used without attribution (tsk, tsk) perhaps the person who licensed AGI-1067 hadn’t seen it… It has been referred to as the Ashby-Tennant supermolecule (possibly from Ashby & Tennant, Mutation Research, 257(1991) 209-27).
People get scarred by high profile failures but sometimes with good reason. I seem to remember Pfizer being obsessed with aminothiazoles and anilines in general ( presumably due to the PGI risk), not many MMP- hydroxamates ever made it – but I’m sure someone can prove me wrong.