Reaction variety – the spice of life?

Chemists join drug discovery organisations with all kinds of synthetic organic experience behind them. But wherever they come from, they’re generally hired to think up and make compounds for testing. More compounds, they realise pretty quickly, are better than fewer compounds. So how do you make more compounds? 

Well, a person can work harder, but that’s only effective up to a point. There’s the hours-in-a-day problem, for one thing, and then there are some synthetic sequences that no amount of time or effort will ever make feasible. So the practical answer to making more drug candidates is often ’take a few good, reliable reactions and beat them as hard as possible’. 

What qualifies as a good reaction? The first requirement is that it always gives you some sort of product - not, perhaps, in the most gratifying yield, but with something there to fish out and send in. The cleaner the reaction, of course, the better. The next criterion is that it can work in the presence of a wide range of functional groups, and following closely on that is the availability of a wide range of starting materials. (It should be noted here that ’availability’, to a drug discovery chemist, does not mean ’available by known routes from the chemical literature’. It means ’on the bench here already or in stock from a reputable supplier who can deliver a five-gram bottle this week’.) 

Examples of reactions in this category are amide and sulfonamide formation, Suzuki couplings (and several other metal-catalysed coupling reactions), amine displacements on activated heteroaromatic rings, urea formation through isocyanates, and reductive amination. All of these lend themselves to preparation of a single intermediate which is then elaborated in one step by a whole shelf full of diverse partners. It’s safe to say that many (well, most) medicinal chemistry organisations would come to a horrible, grinding halt were these transformations to be outlawed. 

Diversity needed 

There’s nothing wrong with these reactions in principle - in fact, using them in this fashion makes a lot of sense. But problems develop when there are too few workhorse reactions, which may well generate compounds that are too similar to each other. Are we at that stage now? 

More than one company has looked over its internal compound bank and found it much less diverse than needed, since too many compounds have been made through the easiest chemistry possible. Heteroaryl-NH-heteroaryl groups are not the answer to every single medicinal chemistry problem, and simply running the list of boronic acids past every place where a ring gets brominated might not be the cure, either.

Another difficulty is that too many of these reactions generate molecules with dubious physical properties. All those aryl/heteroaryl rings tend to make compounds that crystallise very well - too well, in fact. Ureas and sulfonamides have the same reputation. Such compounds can be hard to dissolve in anything useful for dosing: it’s a safe bet that when your compound precipitates out of warm DMSO you’re going to face some development problems.

Other problems might show up among the people setting up all those reactions. For one thing, skills do need to be kept sharp, and running a variety of different chemistries is the best way to do that. And safety seminars aside, medicinal chemists do not actually have limitless capacities for boredom. Running yet another long line of palladium coupling reactions or amine displacements begins, after a while, to feel like working at a sawmill. The blade takes longer to cut through some of the logs than others, but the boards all come out looking about the same.

It’s true that we might not want to spend much time at the opposite end of the excitement scale. Reactions that have to be watched every minute lest they explode are not the answer, nor are elaborate routes involving three-ring-circus rearrangements at the final step. 

But short of these heroics, there are less travelled chemistries that should get more use than they do. It would do us (and our compound collections) good if our molecules were a little less flat, a little less aromatic, and perhaps a little less easy to put together.

Derek Lowe is a medicinal chemist working on preclinical drug discovery in the US