MT-477
Posted by kinasepro on October 27, 2007
From: WO/2006/010127 and recently described as inhibiting PKC.
Go ahead, laugh it up – but hey, it could always be worse:
Journals (beta)Posted by kinasepro on October 27, 2007
From: WO/2006/010127 and recently described as inhibiting PKC.
Go ahead, laugh it up – but hey, it could always be worse:
Great Molecular Crapshoot said
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.
milkshake said
phenols get glucuronidated
kinasepro said
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.
milkshake said
the molecule is an abomination but many natural products are awful too, from the view of classical drug design. And one can get away with lots of ugly things, for the cancer treatment.
nucleardreams said
some phenols can also bind to plasma proteins
oleg said
AstraZeneca thinks terrminal acetylenes are bad…
Still smarting over Tarceva >$$$> Iressa ?
aguy said
Series? This is not a molecule per se—it’s an artificial drawing.
By the way, Capsaicin has phenol,too.
kinasepro said
Series?
weirdo said
Yeah, seriesly.
Green Koala said
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.
GK
Wavefunction said
Talking of obviously toxed-up structures, if you are hosting that dinner on the weekend, just remember that I am allergic to this molecule. Thank you.
EV said
Green Koala,
Could you direct me to the lit. for thiocarbonyls preclinically and clinically being poor/toxic? Thanks.
milkshake said
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.
weirdo said
“thiocarbonyls”
Except, of course, for that PR agonist Wyeth took to Phase III. Exception that proves the rule, I suppose.
BB said
Milkshake (and anyone else for that matter) – in general, what is the problem with compound accumulation?
milkshake said
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
Wavefunction said
Metal chelation is why I mentioned this compound;
http://pubs.acs.org/isubscribe/journals/jmcmar/asap/figures/jm070679if00001.html
sometimes you just wonder why people would even bother, then you realise probably because they have no other choice and for some disorders therapeutic index of 1 is just OK.
DrSnowboard said
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.
.
DrSnowboard said
My mistake, Ashby and Tennant worked for Zeneca…
I’ll get my coat.
DrSnowboard said
http://www.soci.org/SCI/groups/fin/2007/reports/pdf/NigelRogers.pdf