Derek Lowe09.06.07
Drug company chemists are divided into two tribes. There are the medicinal chemists, who make small amounts of many different compounds in their constant quest for a good one, and the process chemists, who take those few good ones and find ways to make whopping batches of them. It's easy to be reminded of the philosopher Isiah Berlin and his division of thinkers into foxes (who know many small things) and hedgehogs, who know one big thing. Process chemists are hedgehogs, and they have every reason to be proud of it.
It's risky to generalize, but there are probably net personality differences between members of the two groups. Medicinal chemists tend to solve their scientific problems by moving on to something else. There's always another analog to be made, and another project to work on if the current one dies. The process chemists don't have that luxury. While they're always trying out new routes, their end products are (by definition) important compounds, which are not going to go away. They have to be dealt with, and what's worse, there are almost always serious deadlines for delivery. It's silly to make discovery chemists work against a strict timeline, but the process labs do almost nothing else, and that takes a different sort of outlook on life. "Fast and methodical" is not a common style combination, but it's what you want in those labs.
Likewise, the chemists in each area have different priorities. Medicinal chemists are famous for not caring about reaction yield -- my own take on that has always been that there are only two yields for a new analog: "enough" and "not enough." But for process groups, yield (reproducible yield, that is) is the single biggest factor. They'll try all sorts of things to achieve it -- well, anything unless it makes the compound harder to purify, or anything that's too expensive, or anything that might be toxic and carry through to the final product. Working under these restraints is the heart of what it means to do process work. The med-chem gang, though, tends not to be very picky about what sort of chemistry they use; "any weapon to hand" is the rule, and damn the cost or the craziness.
The process labs generally laugh last, though, since the huge majority of med-chem routes to drug candidates are junked. Sometimes they're tried out on scale and found wanting, but other times they don't even make it off the process lab blackboard. There are some obvious sticking points, little things like stoichiometric amounts of mercury salts or violent volcano exotherms, but one of the biggest deal-breakers is plain old chromatography. The med-chem labs think nothing of sending their compounds down the HPLC or a regular column that's relatively huge compared to the amount being cleaned up. But scaling that up can be a horrible experience. The process labs will do it if they have to, but they'd much, much rather crystallize something out (or better yet, use it as is) than run a column. Another classic pitfall is reproducibility. Many medicinal chemists wouldn't care about the difference, but a reaction that gives 80%, again and again, is worth much more than one that gives 90% half the time and 70% the other half. If you're working under the eye of the clock, you'd better know how much compound is going to come out the other end of the tube.
So how do these groups get along with each other? Surprisingly well, in my experience. I think it's because they speak the same language of organic synthesis, but to different ends. They can appreciate each other's work, while being glad that they don't have to do it themselves. Companies vary, though, in the ways that they fit these people together. In some organizations, process chemists start sitting in on the team meetings fairly quickly, under the forewarned-is-forearmed theory. In others, however, the discovery chemists hardly see their counterparts at all. The latter arrangement does lead to some "throw the problem over the wall" behavior, but to tell the truth, process chemists are used to that sort of thing. Many of them take pride in being able to handle whatever craziness the med-chem labs come up with.
Which technique is best? I'd have to vote for the early warning system, although you don't want anyone from process sitting in too early. The constant zig-zag of discovery work will drive them crazy: by their standards, molecules and their chemistry are always getting abandoned before they've even been properly started. Make up your minds, already! I'd recommend opening communication later in the project, after a lead series has been firmly settled on. When a molecule really starts coming to the front of that pack, seeing what got tried out in the early work can be a real time-saver. Every organic structure has a sort of personality (surly and hostile, for the most part), and it's good to know what it will and won't put up with. This sort of thing is supposed to make it into the package that gets handed on as a compound moves forward, but (as in every such transfer) there are always details that get lost.
There's a possible downside of too much contact between the two groups, though. Just as the process chemists can get scientific whiplash from seeing how quickly the discovery people drop things and move on, there's a danger in the other direction. The medicinal chemists, constantly hearing about all the things that the process people can't or won't use, might find themselves tailoring their own work (and their own ideas) too much toward what might be acceptable later on. When I brought up this topic on my blog, I realized from the comments and mail that came in that this might well have happened to me along the way. In a rewrite of the old marriage advice, I'd always figured that it was just as easy to use innocuous routes to my analogs as it was to use the troublesome ones, but I'm rethinking that advice.
We all, process and medicinal chemists alike, work with enough extra weights and chains tied around us already. If you try to make one of them too much like the other, you can end up with the ever-popular worst of both worlds: trying to make active SAR compounds while working under the restrictions of efficient scale-up chemistry. There's probably not enough room left in that space to do the job that needs to be done, not on some projects, at any rate. So while I'm not going to switch over to using exclusively cadmium, lead, and mercury intermediates, I do think I'll loosen up a bit, even at the cost of giving the process people a hard time later on. After all, that can only happen with a serious clinical candidate, and the more of those, the better.
It's risky to generalize, but there are probably net personality differences between members of the two groups. Medicinal chemists tend to solve their scientific problems by moving on to something else. There's always another analog to be made, and another project to work on if the current one dies. The process chemists don't have that luxury. While they're always trying out new routes, their end products are (by definition) important compounds, which are not going to go away. They have to be dealt with, and what's worse, there are almost always serious deadlines for delivery. It's silly to make discovery chemists work against a strict timeline, but the process labs do almost nothing else, and that takes a different sort of outlook on life. "Fast and methodical" is not a common style combination, but it's what you want in those labs.
Likewise, the chemists in each area have different priorities. Medicinal chemists are famous for not caring about reaction yield -- my own take on that has always been that there are only two yields for a new analog: "enough" and "not enough." But for process groups, yield (reproducible yield, that is) is the single biggest factor. They'll try all sorts of things to achieve it -- well, anything unless it makes the compound harder to purify, or anything that's too expensive, or anything that might be toxic and carry through to the final product. Working under these restraints is the heart of what it means to do process work. The med-chem gang, though, tends not to be very picky about what sort of chemistry they use; "any weapon to hand" is the rule, and damn the cost or the craziness.
The process labs generally laugh last, though, since the huge majority of med-chem routes to drug candidates are junked. Sometimes they're tried out on scale and found wanting, but other times they don't even make it off the process lab blackboard. There are some obvious sticking points, little things like stoichiometric amounts of mercury salts or violent volcano exotherms, but one of the biggest deal-breakers is plain old chromatography. The med-chem labs think nothing of sending their compounds down the HPLC or a regular column that's relatively huge compared to the amount being cleaned up. But scaling that up can be a horrible experience. The process labs will do it if they have to, but they'd much, much rather crystallize something out (or better yet, use it as is) than run a column. Another classic pitfall is reproducibility. Many medicinal chemists wouldn't care about the difference, but a reaction that gives 80%, again and again, is worth much more than one that gives 90% half the time and 70% the other half. If you're working under the eye of the clock, you'd better know how much compound is going to come out the other end of the tube.
So how do these groups get along with each other? Surprisingly well, in my experience. I think it's because they speak the same language of organic synthesis, but to different ends. They can appreciate each other's work, while being glad that they don't have to do it themselves. Companies vary, though, in the ways that they fit these people together. In some organizations, process chemists start sitting in on the team meetings fairly quickly, under the forewarned-is-forearmed theory. In others, however, the discovery chemists hardly see their counterparts at all. The latter arrangement does lead to some "throw the problem over the wall" behavior, but to tell the truth, process chemists are used to that sort of thing. Many of them take pride in being able to handle whatever craziness the med-chem labs come up with.
Which technique is best? I'd have to vote for the early warning system, although you don't want anyone from process sitting in too early. The constant zig-zag of discovery work will drive them crazy: by their standards, molecules and their chemistry are always getting abandoned before they've even been properly started. Make up your minds, already! I'd recommend opening communication later in the project, after a lead series has been firmly settled on. When a molecule really starts coming to the front of that pack, seeing what got tried out in the early work can be a real time-saver. Every organic structure has a sort of personality (surly and hostile, for the most part), and it's good to know what it will and won't put up with. This sort of thing is supposed to make it into the package that gets handed on as a compound moves forward, but (as in every such transfer) there are always details that get lost.
There's a possible downside of too much contact between the two groups, though. Just as the process chemists can get scientific whiplash from seeing how quickly the discovery people drop things and move on, there's a danger in the other direction. The medicinal chemists, constantly hearing about all the things that the process people can't or won't use, might find themselves tailoring their own work (and their own ideas) too much toward what might be acceptable later on. When I brought up this topic on my blog, I realized from the comments and mail that came in that this might well have happened to me along the way. In a rewrite of the old marriage advice, I'd always figured that it was just as easy to use innocuous routes to my analogs as it was to use the troublesome ones, but I'm rethinking that advice.
We all, process and medicinal chemists alike, work with enough extra weights and chains tied around us already. If you try to make one of them too much like the other, you can end up with the ever-popular worst of both worlds: trying to make active SAR compounds while working under the restrictions of efficient scale-up chemistry. There's probably not enough room left in that space to do the job that needs to be done, not on some projects, at any rate. So while I'm not going to switch over to using exclusively cadmium, lead, and mercury intermediates, I do think I'll loosen up a bit, even at the cost of giving the process people a hard time later on. After all, that can only happen with a serious clinical candidate, and the more of those, the better.