Predicting Pharmacokinetics

There are a lot of challenges in drug discovery and medicinal chemistry, but it is safe to say that most of them stem from trying to make these compounds work inside human beings. Not surprising as we are putting small molecules into a highly complex system that no one fully understands and expect them to work to cure what ails without messing anything else up.

Well, no, that is not strictly true. We don’t expect that. We’d like it to happen, but it never does.

As the established wisdom goes, efficacy is easy, but PK is hard. With the cost of developing drugs, it is not surprising that people have tried to come up with some kind of predictor to help point us in the right direction. The most well known in medicinal chemistry circles is Lipinski’s Rule of 5, which even has its own Wikipedia entry. That gives me a warm and fuzzy feeling for some reason. Other examples exist, such as Gleeson’s ADMET rules of thumb. What they share is a relative simplicity and a way to relate what you are trying to achieve to something a chemist in the lab can control – in other words, what changes you can make to your molecule to make it more acceptable.

This came up with me now because, while tiudying my desk (yes, it does occasionally happen), I came across an article out of Pfizer from Ted Johnson on the Golden Triangle to optimize clearance and oral absorption. In the spirit of the previous mentioned, it attempts to bring properties of the molecule (in this case log D and molecular weight) and find trends to indicate how these relate to the important pharmacokinetic properties of clearance and oral bioavailibility. In fact, they did find some trends and call it the Golden Triangle Rule, where the compounds that display the best PK properties fall within a triangular area of a graph of MW against log D, with an apex at MW=450 and log D ~1.5 and a baseline at MW=200 with log D between -2.0 and 5.0. So again, we need low molecular weight compounds of just the right polarity, though it is interesting that a lower molecular weight gives you more leeway on the range of polarity you can get away with. Though the authors do point out there are compounds within the triangle that fail. This is just a guideline, despite the name.

These are all only predictions and the trend of screening compounds for undesirable properties earlier in the drug discovery program will continue, despite how practical results often ruin a perfectly good hypothesis.

Of course, the problem with a lot of these techniques is that in order to reach an optimum molecular weight you have to remove the parts of the molecule that give it its potency, making it perfectly acceptable but also perfectly useless. But that is what makes a medicinal chemist’s life so interesting.

Exciting New Things

Some exciting things happened this week. They might seem small to some of you who have seen it all before, but I thought it was all rather fun.

First was I got added to the blog roll at In the Pipeline. I think Derek is pretty generous in adding chemistry-related blogs to the list, but I appreciate it all the same and note that I had a record number of visitors yesterday. Broke the record by a couple of orders of magnitude, in fact.

The other one was we got a new toy in the lab – an Isco CombiFlash Rf. They got one in the next lab over where I used to work, though I never got to play with it. There were a couple around the building here, but I was still using the old Companion, a rather crusty work horse still separating away and doing a good job of it. But I knew there was money for a new one and it finally arrived, set up in double quick time too.

I took it for a test drive today and was impressed by the ease of use, how straightforward everythng was – and how it took care of things that you might have otherwise forgotten – such as priming lines with the new solvent. I was a little surprised that it did not come with a couple of racks for 16mm test tubes and an adaptor for the small solid sample cartridges would have been nice too. I know, we can just buy some, but aren’t these the basics? Apparently not.

The arrival of a new instrument like this always awakens talk of the days of yore when we didn’t have such things and it was three columns at a time, all packed by hand, collected by hand, a thin layer of silica over everything, except where you’d spilled a bunch of hexane pouring it into the top of the column.

There’s some nostalgia there, for a simpler time perhaps, but you can’t go back, not once you have had everything nicely and efficiently done for you. Why would you want to? Automated purification systems like Isco’s have made our day-to-day work a lot more efficient, as well as less messy and much safer. They have really joined the rotary evaporator as lab standards.

From time to time, I run across someone who says they actually prefer the old way. I smile and nod, slightly in awe of their dedication to old methods (which they usually claim give superior separations). And then I go right back to my Isco and run three separations while they get their next one set up.

The Balancing Act of Selectivity

In an ideal world, where we can rationally design our drugs to target only the one receptor or enzyme we aim for and there are no side-effects or adverse reactions, we could find the ideal compound for every application and then dial up the prescription depending on the patient – the ultimate personalized medicine.

Meanwhile back in the real world, the messy, non-selective and unexpected actions of drugs reign. And even where you see good selectivity by a drug, in many cases, especially in the cancer field, the therapy is found to be ineffective, because the disease – the cancer, the virus, whatever – has found a way to get along without that component that was previously thought indispensible.

In short, it has become at least useful to see exquisite selectivity as a missed opportunity to get two birds with one stone. This is particularly true in the kinase field, where many hopes for treating cancer have been vested. A recent article by Richard Morphy in the Journal of Medicinal Chemistry talks about this. A good number of drugs were in any case non-selective or at least with limited selectivity, but it turned out that as long as you got the right off-target kinases as well as your one, there were not any ill-effects. In fact, Morphy notes there has been an increase in programs specifically looking for multiple targets from a single drug.

This is an immensely difficult thing to achieve, as each change to a molecule will result in a cascade of changes in the inhibitory profile, which is overlooking the changes that will be seen in physiochemical and, as a result, pharmacokinetic properties. So actually tuning the activity to exactly what you want is nigh on impossible and in most cases, you have to look at what you found and take your best shot at which one is “the best”, as it is not a trivial matter to determine how much each activity against a particular kinase contributes to the overall efficacy of the drug. It is quite common, for example, to find you have binding with a particular kinase but when you run a functional assay, you find that the compound has little or no activity. Adding in the complexities of the human body in all its pharmacological glory makes determining what you just did when you gave someone that drug tricky.

But when we make a kinase inhibitor, we don’t only have to worry about other kinases that our super-drug might target. Oh no, that would be too easy. It might also inhibit – or even stimulate – activity elsewhere in the complex human machinery. Drug discovery programs often look at cytochrome P450 inhibition, as that is a huge red flag for a drug due to the potential for drug-drug interactions to cause problems (see St John’s wort for an example). But it is much more wide spread than that, according to research by Brian Roth and Brian Shoichet and reported in a recent C&E News, research that may go some way to explain some of the side effects drugs have.

So we see that attempting to tease out amazingly selectivity over one kinase from another is a thankless task, given how many other things it may end up interacting with. All we can really do is try to avoid interactions with particularly important targets and then hope for success in the toxicology screens. That sounds a bit cavalier, but in reality, the clinical effects of these compounds will be muted by other factors such as protein binding, clearance and the like. And at the end of the day, what other choice do you have?

Pzifer Closes Both Wyeth Sites in North Carolina

When you are looking for a new position, one of the things I was advised to do was make a list of the qualities in a company you were looking for: size, commute distance, type of work, ability to telecommute, etc., etc. One of the items on my personal list was ‘not involved in a merger’. So I didn’t really look too hard at openings that popped up under Wyeth’s name. The only one that springs to mind now was in Sanford anyway – a little far on the commute for me and in any case, I was not a good fit for the position.

Turns out that was the right move, as both the site here in Research Triangle Park and the one at Sanford made Pfizer’s list of sites they are closing. A nicely organized list is here. Bloomberg was where I read about it first; another good piece is on Fierce Biotech, linking to several related stories.

It is sad news for everyone, though I don’t think anyone is surprised there are site closing. Part of why they announced the deal was the potential cost savings as overlap between companies is eliminated ($4 billion annually, they estimate), as well as strengthening Pfizer’s position on biologics and improving their global reach and diversity. On the face of it, it appears this is a good deal for Pfizer, although those eliminated in the name of removing overlap will be unlikely to agree. It occurred to me that making the biggest pharmaceutical company in the world even bigger just made the world of drug discovery a little smaller.

Unemployment for Chemists

The current C&E News has an article (actually a series of articles) on unemployment in the chemical industry. While the country hits double digit unemployment, ACS members are experiencing unemployment at 3.8%, up from 2.3% last year. Aside from my reaction to the number (something like “only 3.8%?!”), it is at least clear that it is a rising problem and these are record unemployment levels for ACS members.

A simple glance at the business pages tells the same story. Big Pharma has laid off a lot of people in the last year, whether part of a mega-merger or just to streamline and cut costs. The C&E News article says something I myself have said – that eventually companies have to stop cutting costs and start making things again, that they will need people to do that.

I started wondering where exactly they would get the people to do that, assuming that they do. I foresee a modest growth in the companies themselves – they can’t stand still while new talent comes on the market, but they have spent all this time and money streamlining their operations. It would seem foolishness to undo all that effort. So it would seem logical that they would do what they can in-house and outsource the remainder. That in turn would suggest a further spur to the growth of research activities in China, India and Eastern Europe. The infrastructure and knowledge is growing in these places – any American entrepreneurs wanting to get in on this potential market will have their work cut out competing against the cheaper work force available overseas. Some will undoubtedly profit from such deals, whether because the pharma company doesn’t want to let the project too far away or because of a history of success between the two entities – it is sometimes worth paying more for something, especially if you have built up a level of trust with the people doing the drug discovery for you. It does feel like it will be a challenge for small companies in the U.S. and there may be a period of transition while they adapt to the new way of doing things in the reborn economy. I can imagine a number of U.S. companies acting as a liaison between Big Pharma and the overseas researchers.

The bottom line here is that a lot of people in research have lost jobs in the U.S. in the last year or two and frankly, I don’t see all those jobs coming back. It seems a terrible waste that many skilled chemists will be unable to find work in their chosen profession, but I fear that will be the harsh reality.

First post in a while

I’ve been in my new job for three months now. It is going pretty well, I think, making progress and settling in. I’m also enjoying the work and it is good to be at the bench again, making use of those now-not-quite-so-rusty synthetic skills. So all is good (I even get to play the occasional lunch time soccer game here), but it does mean I have a little less time for Other Things. A couple of things have suffered and this blog is one of them. (My wife will tell you the house tidiness is another).

I started the blog after I got laid off and now I am working again, it is natural that there should be less time to post. Combined with the issue of exactly what to talk about, the poor thing has languished since the euphoria of landing faded.

Well, I am going to try and update a little more often than once every 3 months. Hopefully with something to interest people. I did figure this blog to be ‘job-related’, so will keep the posts on the subject of chemistry, the pharmaceutical industry and the like. The job market should be a topic of interest for a while too, as we often talk about the things we don’t have too many of. I did wonder about turning the blog into a sort of diary of my work day, but I think that is a non-starter, as I will be forever debating about whether I should talk about something I am doing in lab out in a place where anybody might read it.

One of the other things that lagged with my re-remployment is my twitter account. I logged into it yesterday for the first time in … well, let’s say I was looking at it as often as I was blogging. I am going to start checking in there too, with a greater amount of my non-work side allowed out onto the social network. So maybe I will see you over there too.