KinasePro has a bit of discussion going on about halogen bonding in his Cl—-O thread. So I thought I could chip in my tuppence worth, being someone who up till now has had little real-life exposure to the whole concept. On series that I have worked, there have been times when adding a chlorine to an aromatic system has resulted in a large (~10-fold) improvement in activity, but this wasn’t ascribed (at the time) to any special halogen bonding effect. Maybe we put it down to the creation of a nice, snug fit with a lipophilic pocket. Maybe that extra slice of LogP went a long way….who knows.
The question I would be interested in answering is this - given a set of SAR data, and without an X-ray structure, how would you determine/suspect if you did have a halogen bonding interaction?
I was reading the latest paper from Bill Denny (DOI) on inhibitors of PI3-kinase alpha, and was checking back through a few of the references. I found this paper (DOI) from Astellas (or Yamanouchi as it was when this work was done), where they had a nice little SAR table with substituents that might help decipher if a halogen bond was involved.
The methyl substituted compound comes in at 6nM, but the chloro analogue beats it hands down at 0.8nM (approx 8-fold improvment), whilst the bromo version is 0.3nM, a whole 20 times better. How much confidence would you have in declaring this a halogen bonding interaction? I don’t know what to make of the nitrile analogue 8h….maybe that indicates some other reason is responsible for the potency increase, unless of course the nitrile is behaving as a pseudohalogen. Whilst no X-ray structures are available, the Denny paper gives some docking images of the bromo compound, looking as if the bromo is within striking distance of the carboxylate side chain of Asp964.
So, what do we make of it all?
Last week Synta/GSK announced a deal that saw GSK pick up rights to STA4783 (release), with a headline figure of $1.1bn for the deal. The structure of STA4783 can only be described as unusually nasty - in these times of molecularly targeted therapeutics, SBD, high-throughput structural biology etc. this compound looks like a real throwback.
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Genentech/OSI today announced US sales of Tarceva were up 1% compared to Q3 2006. This does however include an usually large volume of product returns [which I guess means that they shipped product earlier, accounted for those revenues and now have to take them back for product that didn't actually sell]. Gross sales were up 12% compared to Q3′06, and OSIP/GENE reiterated their forecasts for annual sales of $855-$860m (up from $650m in 2006).
Q3 reporting season is only starting - I’ll update the spreadsheet when all the dust has settled.
This morning Exelixis announced that their ADAM-10 + MMP-2 inhibitor XL784 was not efficacious (release). They were looking into reducing proteinuria in patients with diabetic nephropathy, and it was touted as a potential blockbuster. It seems to come from US60/388326 (WIPO), and like most (all?) MMP inhibitors it is a hydroxamic acid (generic form shown below).
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KinasePro sends the hit counter skyward….I was getting hits from some unusual places (Boston Consulting Group spring to mind). Ta!
It’s been a long time since the last nibble - this new one comes from Zentaris and their academic collaborators (DOI). They have been preparing ghrelin ligands, which they say might be useful in the treatment of disorders for which growth hormones are usually required (ghrelin agonists), and also for potential (and lucrative) use in appetite control (ghrelin antagonists). They describe how the ligands that they prepared had effects on appetite, but not on growth hormone secretion, which they say indicates the existence of ghrelin receptor subtypes, although they managed to word this in such a fashion that I didn’t totally follow. As far as I can tell, there are currently no ghrelin antagonists in clinical trials - but there are a number of ghrelin agonists in the clinic examining their possible use in stimulating appetite (for anorexia and cachexia).
Anyway, chemistry-wise I liked the prep of the triazoles - had never seen this method before (not that I knew an awful lot about triazole synthesis).
Treatment of the N-Boc amino acid amide with Lawesson’s reagent yield the thioamide, which was then cyclised with an aryl hydrazone to yield the desired triazoles. This did however require a stoichiometric quantity of mercury acetate, which must have made these compounds a bit of a pain in the arse to work with. I have never used Lawesson’s reagent…I guess it’s a bit (a lot!) smelly?? Even more of a pain to work with then…..
I have added a few papers to the literature / reading list (over there =====>).
The first 2 new ones (18 and 19) cover some ground on toxicology, the third (20) is a more recent publication on modulating amine basicity. All well worth a few minutes of your time.
In my new spirit of sharing, here is a link to a spreadsheet that I have put together on data covering the commonest types of cancer.
Link - [EDIT - Updated spreadsheet now available]
It covers data on incidence, median ages at diagnosis and death, survival, disease stage distribution on diagnosis (with 5-year survival), and cases per year in the US and the EU. Some data are not available (or, more likely, I have not been able to locate yet), such as a breakdown of the incidence of the various forms of leukemia in the EU.
The data was mostly sourced from seer.cancer.gov (LINK) (for the US), and various pieces of literature on incidence of cancers in the EU (such as this paper here from Boyle and Ferlay). Most of the data seems to cover the years 2000-2004.
Enjoy!
For your delectation…any bets on the Q3 sales of Tykerb?
Raw data link…
Data all culled from 10K’s and quarterly financials.
