Hot on the heels of the review of fluorine in med chem from Hagmann at Merck comes this JMC paper, also from Merck (DOI) on the work that they have been doing on generating inhibitors of kinesin spindle protein as alternatives to more commonplace anti-microtubule agents such as Taxol/Taxotere.

To summarise their efforts into a small scheme…

Their initial lead had poor in vivo activity, so they went back, lopped off the difluoro amino side chain and slapped on a piperazine onto the urea.  This showed too much inhibition of hERG, so they reintroduced a polar substituent onto the dihydropyrrole, which showed reduced hERG activity, but which was now a better substrate for Pgp efflux (one of the problems that limits the taxanes).

Changing the substituent on the piperazine solved this problem, but the cyclopropyl substituent was a time-dependent inhibitor of CYP3A4 (apparently a common issue with such groups), whilst the beta-fluoroethyl substituent was found to generate a toxic metabolite in vivo (fluoroacetate generated by dealkylation of the amine).  Switching the fluorine from the ring appendage into the ring itself gave a compound which ticked all the right boxes - there is a whole load of other information in the paper which makes it well worth reading.

I have added the recent paper from Hagmann (Merck) on “The Many Roles for Fluorine in Medicinal Chemistry” to the literature list, which covers some advances made in the synthesis and use of fluorine substituents in med chem, with a few case study type examples thrown into the mix.

Also added is a summary of mitochondrial toxicity in pre-clinical discovery and development from Dykens and Will at Pfizer, and a nice little piece on preclinical in vitro studies for selecting drug-like compounds from Li (link).

…..is back online.

http://kinasepro.wordpress.com/

A recent paper in JMC from academic groups in Texas and Seattle (DOI) are looking at inhibitors of malarial dihydroorotate dehydrogenase (also patent app made WO2007/149211). Malaria seems to be something of a cash cow for academic groups the world over, with numerous funding bodies supporting efforts in this area - fair play I guess, with this being one of the biggest killers around. What interested me about this work was the use of the 2-naphthylamine unit in their inhibitors. I suspect that most med chemists would have serious worries about using this unit in a drug - 2-napthylamine is a known carcinogen, and the potential for the formation of metabolites of this substituent would give us some concerns - and a serious effort to replace it.

First off a bit of the synthesis end of things….

Condensation of the aminotriazole with the ester yield the desired pyrimidinone, which is chlorinated with POCl3 and then aminated, so fairly standard stuff. So they found that when R is methyl and R1 is H that pretty good inhibitors can be prepared - but reliant on that nasty 2-naphthyl unit [or even an anthracene, which has DNA intercalator written all over it].

So, now the efforts they took to replace it!. Going to the phenyl version gave inactive analogues (always a bit of a worry when trimming down a huge greasy piece causes activity to fall off a cliff), and the quinoline analogues were pretty poor also at around the micromolar level.

It would have been nice to see some more SAR on the naphthyl replacements - biaryls, some halophenyls (especially 4-chloro, 4-fluoro, 4-bromo, 3,4-dichloro), methoxy, 3,4-methylenedioxy, cyano, 4-trifluoromethyl…….and perhaps some haloquinolines as well, the list could go on and on! Maybe that’s all work in progress, but it does leave a kind of half-baked feeling about the work, which is a shame because like they say in the paper they have identified a highly promising lead candidate, and seeing as the patent priority date is back in June 2006, they have had at least 18 months to fill out that SAR table.

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.

For example, I have recently been looking at some stuff Antisoma (link) have been doing in NSCLC, and thought that I would rustle up a valuation using this second method.

The image above illustrates the principles fairly clearly I think. To some extent you have to use educated guesses of the likelihood of clinical trial success. For example, taking ASA404 - the Phase II NSCLC trial data is split 1/3 - 2/3 between squamous and non-squamous NSCLC. Seeing as Novartis (who have licensed this program from ASM) have indicated that they intend to develop ASA404 in squamous cell NSCLC (Avastin is approved for non-squamous only), this means that a lot of that Phase II data is no longer really relevant to the proposed Phase III program (only 11 squamous cell patients in the 1800mg/m2 treatment arm!). I chose a 40% likelihood of success - therapeutics which have unprecedented mechanisms of action fail twice as frequently as those that don’t. In addition squamous NSCLC is generally shows shorter PFS, and is more aggressive/less survivable that non-squamous, which will undoubtedly make it a tougher clinical nut to crack. Add in the fact that ASA404 bombed in ovarian cancer, and that prostate data was looking a bit shaky……

How then do you decide on an estimate of peak sales? In this case I looked up how much revenue Avastin currently generates (approx 1.8bn USD per annum and still growing), and divided that by 5 (80% of NSCLCs are non-squamous, only 20% squamous). That gives you approximately a market of ~$360m, which converted into pounds is approximately 180m GBP. Since this product won’t be on the market (if ever) for a number of years, I inflated the peak sales to 500m GBP per annum, which will also allow for some off-label use. [What can I say, I was feeling generous!]

The multiplier used next not only allows for sales from multiple years to be taken into account, but also gives extra credit to ground-breaking therapies that will probably have that “X-Factor” - everything from elements of “coolness” and clinical excitement to the reliability of that revenue stream.

Pulling all this together you arrive at a probability adjusted value, which is used to derive the present value (discounted over the number of years to the sales peak). Bingo Bango, you have a valuation. Repeating the process for the other clinical programs, add in the cash in the bank, and it all works out to give you a current share price target.

You can download my spreadsheet from here.

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).

For those of you in analyst mode, you can use Excel to predict the Q4 sales (select the row of numbers plus one additional empty cell - Edit - Fill - Series - Type[AutoFill]).

The predictions come out as follows - Glivec $811m, Sutent $183m, Sprycel $52m, Iressa $54m, Nexavar $109m, Tarceva $258, Tykerb $44m.

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).

It seems evident that corporate flexibility is the order of the day - open a CEDD here,”downsize” a CEDD there - with the result that jobs end up going to countries (China, Singapore) in which GSK can employ people without having to worry about troublesome little staff perks such as a permanent contract, redundancy payments, pension scheme, equity incentive/savings plan and a US/EU sized wage packet, not to mention a stack of employers taxes and high corporation taxes.

GSKs Centre for Excellence in External Drug Discovery has been pretty busy of late - most notably in my mind the deals they have done with Galapagos DPI (asthma, osteoarthritis, osteoarthritis again) and Exelixis (story), and the aquisitions they have made (Domantis et al.). At least if you don’t like the compounds they develop, you won’t be the company handing out the P45s.*

I would like to summarise by saying that I think we are screwed. Time to break out Plan B I think.

**[A P45 is given to taxpayers in the UK when their employment is terminated, and it summarises the amount of tax they have paid thus far for the year in order that their new employer knows what they should be deducting from their wage].