« A Real Genetic Headscratcher |
| How You Doin'? How's Everybody Doin'? »
November 12, 2007
Here Be Chiral Dragons, With Fluorinated Fangs
There’s a saying that you see attributed to all sorts of old humorists, which goes something like “It’s not the things you don’t know that get you, it’s the things you know that just aren’t so”. (I always put it down to Kin Hubbard, but the best case can probably be made for Josh Billings). What you can’t argue about is the truth of the thing, and that truth gets demonstrated at all phases of a drug discovery project.
You see it all the time in the med-chem labs, that’s for sure. After a project has been going a while, a lot of people have had a crack at the SAR, and have made a lot of different compounds. Everyone has put their own facorite groups on, and things have been tried out on all the reasonably accessible parts of the structure. That’s when the myth-making starts – I’ve never been on a project where it didn’t.
“Trifluoromethyl in the 4-position’s a killer – I wouldn’t put anything electron-withdrawing there if I were you”. “You need the R stereochemistry at the benzylic site; those always work better than the S”. “Somebody tried to make the meta-substituted compound – it never worked.” “All the methyl compounds get cleared faster than the fluoros”. This sort of things will sound very familiar indeed to my drug-discovery readers. Anyone who joins a project that’s been going for a few months or more will get all the folk wisdom of this sort that they can stand.
But how much of it is real? In my experience, about half, and sometimes less. Many of these rules of thumb are born from only one or two examples, often as not from the earlier days of the project when other parts of the structure were different. It’s a rare project where you can mix and match with impunity, which means that these rules often outlive their validity. You really have to go back and check up on these things. And sometimes, disturbingly, there’s no foundation at all. This is a real danger in a long-running project with a lot of manpower changes and a long list of compounds. Once in a while you see everyone convinced of something that has no empirical support at all – it’s just something that “everyone knows”. Making compounds to put such superstitions to the test should be actively encouraged.
But depending on the culture of your company, or just your project team, that’s not always easy. Some project leaders ask for (or at least tolerate) a certain percentage of let’s-find-out compounds, which I think is healthy. But in other shops you have to brave well-meant ridicule or outright hostility when you send in analogs that challenge the accepted wisdom. As usual, it’s a question of the odds. If you make nothing but contrarian compounds, you’ll have a lower hit rate than the folks who are following up on the current leads. But if all you do is follow up on the current leads, never looking back or to either side, you’ll miss out on a lot of potentially useful things. Moderation in all things, the man said.
+ TrackBacks (0) | Category: Drug Development | Life in the Drug Labs
POST A COMMENT
- RELATED ENTRIES
- How Not to Do It: NMR Magnets
- Allergan Escapes Valeant
- Vytorin Actually Works
- Fatalities at DuPont
- The New York TImes on Drug Discovery
- How Are Things at Princeton?
- Phage-Derived Catalysts
- Our Most Snorted-At Papers This Month. . .