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March 12, 2007
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Posted by Derek
I wanted to link tonight to the "Milkshake Manifesto" over at OrgPrep Daily. It's a set of rules for med-chem, and looking them over, I agree with them pretty much across the board. There's a general theme in them of getting as close to the real system as you can, which is a theme I've sounded many times.
That applies to things like "Rule of Five" approximations and docking scores - useful, perhaps if you're sorting through a huge pile of compounds that you have to prioritize, not so useful if you've already got animal data.
He also takes a shot at Caco-2 cells and other such approximations to figure out membrane and tissue penetration. I've never yet seen an in vitro assay for permeability that I would trust - it's just too complicated, and it may never yield to a reductionist approach.
I'm a big fan of reductionism, don't get me wrong, but it's not the tool for every job. Living systems are especially tricky to pare down, and you can simplify yourself right out of any useful data if you're not very careful. The closer to the real world, the better off you are. It isn't easy, and it isn't cheap, but nothing good ever came easy or cheap, did it?
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1. milkshake on March 12, 2007 9:21 PM writes...
Thank you for your kind mention, Derek - the Wordpress servers that host Org Prep Daily shall smoke tonight....
Permalink to Comment2. Chrispy on March 13, 2007 2:57 PM writes...
Great site, 'shake,
I was interested to see a few things on your list which I hadn't seen elsewhere, such as acidic compounds being bound by plasma proteins.
I wonder about oral bioavailability testing in mice, though. I mean, Caco-2 is crap, but I wonder if mice are much better. I still see us throwing away which might be perfectly good compounds based on bioavailability in mice.
Does anyone know what the correlation is?
The advent of microdosing should change all this, but it seems like this only is brought in when people get desperate. Perhaps it is too expensive (?)
Permalink to Comment3. A-non-y-mous on March 13, 2007 4:41 PM writes...
Re: Microdosing
Exploratory INDs may have their use, and I looked into it for a while. It lets you get into man quicker by using microdosing, with a maximum microdose of 100 micrograms. This amount may be too little to see any efficacy, and possibly too little to get any good oral data, depending on oral bioavailability, of course. The FDA intends it to be used by companies so that they can have more data available when they need to choose between several lead compounds.
The pathway for an exploratory IND has fewer tox studies, but in the end you of course still have to do them all.
I don't know of anyone going this route, which is why the FDA reminded people about it ~2 years ago. Does anyone know if a company has made use of an exploratory IND? Did they get what they wanted out of it?
And it would end up being more expensive in the end, unless it keeps you from ditching a good project.
Permalink to Comment4. Clark on March 13, 2007 10:13 PM writes...
Several people at my company have expressed disdain for microdosing. They beleive it does not give any useful data. There is a big difference between getting 100 micrograms dissolved in the GI and 100 miligrams, and since half of oral absorption is solubility, you can see the problem.
Permalink to Comment5. Kay on March 14, 2007 6:58 AM writes...
Let's just keep using our existing tools and rules. They are all working fine, and they are based on large prospective data. Last year was the best year for NMEs on record. We spend small sums bringing each NME to market. There is no reason to presume that our methods/rules/tools should change.
Permalink to Comment6. Liquidcarbon on March 15, 2007 4:46 PM writes...
mauveine! :)
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