So for the first time in a while a little chemistry - this is from Hofmann-La Roche and their CB-1 inverse agonist paper (DOI) in JMC. Over on In the Pipeline there has been a fair bit of chatter on whether this whole target class is eternally doomed folloing the Rimonabant disaster - I remain thoroughly agnostic on the matter due to profound ignorance. That aside, I like this neat little preparation of the 1,1-dichlorides.
Not something I have seen before, and always nice to see some of the med chem rules getting ignored (no acetals!).
Its been a while since I posted an updated spreadsheet on kinase inhibitor sales. It has now expanded somewhat to include a bunch of other cancer therapeutics which broadly fall into the “targeted therapies” bracket.
It is available here.
If like me you are interested in entrepreneurship the following might also be of interest
www.evelexa.com - be sure to download the Biotech Entrepreneurs Guide, very useful guide to what you need
Nature BioEntrepreneur - a lot of useful articles from a wide variety of sources on important things to think about when thinking about starting up and getting going.
SlideShare - some kindly people have deposited on this site some PowerPoint slides about a wide variety of start up issues (VC, IP, financing, business plans etc). Try searching for “biotechnology” and it will bring up a load of useful stuff (registration required). In particular I learnt a lot about how VC finance works from here.
Anyone know what the score is wrt to glaxo’s neuroscience research centre in Singapore??? The new centre they are talking about in Shanghai would seem to be doing exactly the same work. Any pointers appreciated.
Last time I posted about biotech valuation (here), the model used was very “bottom-up”; that is, I attempted to put in place estimates of numbers of units sold, unit prices, market penetration, inflation adjustments, development costs, and to use this data to arrive at an estimate of cash flow, which is then discounted by the risks of clinical failure (the rNPV method) to arrive at a valuation. Another approach I have seen used is a lot more rough-and-ready and is far more “top down” - specifically, you start with an estimate (guestimate even) of peak sales and odds of success and use that to directly arrive at a valuation. (more…)
Further to my previous kinase inhibitor spreadsheet, the updated version is now available (LINK). Glivec is still going great guns and showing no signs of slowing, and Tarceva is well on track for blockbuster status (even though it is currently not used in first line/adjuvant settings in NSCLC - LINK). Seems like Tykerb is off to a decent enough (if unexceptional) start although it was never predicted to be a stunning seller ($380m-$700m) (see article from NRDD here).
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Adding to the list of Big Pharma companies that are shedding jobs left right and centre, GSK today announced that jobs will be cut in order to save 700m GBP per annum (from BBC), which is coming close to the amount that Pfizer plans to cut back on every year (which of course cost 10,000 people their jobs). This comes in response to a 4% fall in quarterly profits (to only 1.88bn GBP), on the back of Avandia’s woes (although I would have thought that the recent weakness of the USD had a large part to play as well). Of all Big Pharma, I would have liked to have believed that GSK would escape from some of the bloodlust that seems endemic in executive circles, but with pension companies and analysts on their back about a stagnant share price, I guess they thought they had to do something spectacular where real people actually started to get shafted (apparently a fairly massive share buyback and hiking dividends didn’t quite do the trick).
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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.
