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).
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.
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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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.
