Life of a Drug

So rather than do a Chemistry tutorial today, I thought I would just go over the whole drug discovery process.

See the only thing you hear about drugs is that they are too expensive and old people can't afford them, but what you don't hear is how long it actually takes for a drug to become a drug. The entire process is very long, and my job is right near the begining.

First what you need is a biological target, some enzyme or protein in the body that is causing a chain reaction of events to occur. In the begining you usually have no idea what that target actually does until you develop a compound to tell you that information. Let's take Vioxx for example, seeing as that is a pretty high profile drug.

Before Vioxx, the only non-opiate painkillers available were Acetyl Salcylic Acid (Aspirin), Acetominohpine (Tylenol), Ibuprofin (Motrin) and Naporxin (Alleve). Now all of these drugs act on both the COX1 and COX2 receptors which is part of the pain and inflamation pathway. Acetyl Salcylic Acid is way more potent for COX1 than COX2 and the others are still more potent towards COX1 over COX2 but to a much lesser degree. However, it is know that by inhibiting the COX1 pathway, you tend to cause stomach ulcers. Which is why taking alot of these medications all the time is not good for you.

So that's why COX2 selective inhibitors were developed, to avoid wearing away of the stomach lining, so that arthritis sufferers could continue to function without damaging there stomach. However, unbeknowst to the companies that selectively targeting COX2 can result in increased heart risk, hence why they're in the position that they are in now. Anyway, this is just a very long winded way of telling you how people come about targets. There are many other ways targets are chosen.

Okay so once the target is chosen, this is where chemistry jumps on board. What usually happens is that a large library of compounds is screened against your target and activity is measured. This usually gives you a few hits, where the chemists then remake those compounds and retest them in the assays to see if they are real or not.

These real hits are then handed off to the medicinal chemist that's me. It's our job to optimize the compound so that it SELECTIVELY acts on our target. The reason you want this selectivity is because the more selective the compound the less side effects. We do this by taking the hits and making structural changes to the molecule and retesting them in the assays. We continue to fine tune the molecule until we have achieved certain desired properties. As I said before you want the compound to be selective for your target, to this end, the molecule is tested against a variety of KNOWN problem targets to see whether or not it is active against them. Also, nowadays consumers want to take a pill rather than an injection or supository, therefore your molecule needs to be absorbed by the body, taken up into the bloodstream, and circulated through your body, and eventually excreted. The longer the compound remains in your system the less often you have to take a pill. Compounds that are excreted quickly mean that you have to keep dosing (ie 2-4 times a day or worse). The ultimate desired compound is one where you can dose once a day, people seem to be able to remember to take a pill once a day.

Once we've sufficiently optimized a compound, the real fun starts. You need to test the compound in animals to see if the desired effect is observed. In other words you need to measure the efficacy of your compound, is it doing what you want it to. This also means you have to scale up production of the molecule and this is where process chemists come into the picture. There job is make large quanities of the material for testing. These guys/girls are the real chemists, they know how to do some serious chemistry. Us medicinal chemists are really only concerned with testing the final product not optimizing how it's made.

Then the molecule has to go through toxcity studies which are also done in animals, and then finally it can go into man. It then has to go through 3 phases of man studies, which are known as Phase I, Phase II, and Phase III. Depending on what type of area you're working in this can take anywhere from 4-10 years. Phase I studies are just testing out dosing strategies and your trying to determine the optimal dose. Phase II is a more comprehensive study, where you nail down your dosing regiment and also you get some efficacy data (usually known as a Phase IIb study). Phase III involves a WHOLE lot of patients, and this is where your drug either makes it or breaks it. Here it needs to show efficacy, it needs to work in a statistically significant portion of the study (ie it needs to work better than placebo).

The basic statistics of the process is that 1 in 10 compounds that make it into man actually successfully become a drug. There are just so many things that can happen along the way. That means that 9 out of 10 times all the money and effort that have been put into a particilar compound is completely wasted. Most of the time the compound falls out in Phase III which is the most expensive of the studies. Overall, it takes somewhere along the lines of 7-10 years from inception to drug, does that help you appreciate pharmaceutical companies anymore?

I know Pharmaceutical companies are protrayed as these great big evil corporations that feed on the sick and elderly, but my personal opinion is that at least there trying to do something good. Whereas a lot of other corporations out there are just taking your money for absolutely nothing. At least Pharmaceuticals are helping people.

Anyway, so there you have it. That is the basic gist of the pharmaceutical industry. If you've made it this far, and you're still awake and you have any questions, go ahead and ask away.