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.

My Job Search Odyssey

I have been meaning to give a short run-down of my experience in the job market this past few months.

The first couple of months after I got laid off were difficult to say the least. I was not really ready (read: not at all ready) for the new job market and suddenly, there I was, in the middle of the worst economic downturn in a good while, in the fray, trying to fight the good fight. There were no postings for anything in my area in a similar vein. Looking to advance my career wasn’t realistic; it was more about which direction would I end up going. As much as I love doing chemistry in the lab, I had to entertain the idea that I would be doing something else entirely.

Fortunately, even as I was keeping my options open, things seem to beginning to turn around. I got calls from recruiters, but more importantly, I got calls from employers, looking at me more closely. One of the positions was definitely an advance on my career too, so that was encouraging. The other I will talk more about in a moment.

There followed a lull after that flurry of excitement. I looked at some other positions, though each would require some transitioning to a new area for me. Realistically, with the current market, the employers are probably finding plenty of candidates with the profile they are looking for already complete. Transitioning into a new area right now will require some luck and some creative networking.

As it turned out, trying to advance was difficult too. I never got to interview for that position: I lost out to someone with more recent experience in the therapeutic area (I had some, but it was from my graduate school days, so not exactly state of the art). That was disappointing, but not that surprising really.

So then, there was a bit more excitement again. I had THREE separate calls from recruiters, all asking me about the same job. All seemed eager to have me on their team. That was encouraging. More importantly, I made it to a milestone for my job search: scheduling a phone interview with the hiring manager.

That phone call came along. I was, I admit, a little nervous about it. It had been a while since I was in the hot spot. But in a sense, I had been preparing for it for several months now, getting together my values and value, ready to present myself as the dedicated and knowledgeable chemist, eager to get back in the lab and get to work, all while learning something new. And as it happened, the phone call went very well and I was invited to come on-site to RTI to talk in more detail.

It had been drilled into me to be well-prepared for an interview when it came and I was not going to be caught out. I reviewed the difficult question lists, watched YouTube videos on interviewing, looked over my own career history so I would be familiar with the work and that I would have a ready answer for any question.

It turned out that I did not really need such thorough preparation. The interviews I had were all quite pleasant, as much about informing me about the position as it was about finding out about my hidden depths. It felt for the most part like a conversation between colleagues, no set agenda, no long and probing interrogation, just a comfortable chat about life in chemistry. In some ways the lack of structure caught me out a little and I thought later that I had not sold my own strengths as well as I could have done. But the feeling afterwards was mostly positive, no awkward moments or long silences. So I was optimistic, though I was not quite sure. They did not give me any real indication at the end of the day, just that they would let me know in a few days.

I made sure I thanked everyone afterwards. I thought it might be decided quickly so I sent them by email (even though everyone told me hand written notes are key). I thought of sending additional hand written ones, but waffled on it for a while (was it over-kill?) and then got busy with other things. By the end of the week, I hadn’t heard anything, so I got in contact with my HR contact. She told me she expected to hear by the end of the day or Monday. Then, literally 30 minutes later, she calls back and offers me the position! So that was settled – I had found my new job.

Looking back, the key things that got me this position were:

1. The support and advice of my networking group and outplacement consultants. They got me ready to meet the challenge when it came.

2. I found the job posted on CareerBuilder, but I am not at all confident I would have gotten the job if I had just applied and sat back and waited. I found the name and made myself known to the recruiter with a personal connection, letting her know that I had applied and was interested. That put me in her mind as she was assembling her list of candidates. Of course it helped that I met all the requirements of the position, but I am sure I was not the only one.

3. Inevitably, a network contact. You never can be sure who it is going to be. The fellow in this case had worked at RTI but I did not know it. You never know when someone will call up someone you know to ask about you. You want them to say nice things. So be nice to your colleagues and network contacts, offer to help them out, be ready to follow through with that.

I’m going to end this ramble now: lunch time is over, got to get back to work.

Learning from UCLA

This week’s Chemical & Engineering News has an amazing article on the recent tragic death of Sheharbano (Sheri) Sangji, a research assistant in the lab of Professor Patrick Harran at UCLA. If you have not read it, I highly recommend that you do.

This incident in particular has brought academic labs under the spotlight with regard to their attitude to safe practices in the lab. Many of my colleagues have war stories from their times in academia, talking about procedures that would not be tolerated in an industrial setting. Occasionally people talk about how it was because we were young and inexperienced and sometimes it is about how much money that there is to spend on safety, but generally I think most feel it is about getting results from their graduate students in a short time frame. It is in the interest of both student and professor that the work being done produces papers. The result: long hours and lax safety practices.

In some ways, though, it is a surprise that Sheri’s accident involved t-butyl lithium (tBuLi), which is a highly pyrophoric material (meaning it spontaneously catches fire in the air). When handling such a known danger as this, most people would take extra precaution, treating it with the proverbial kid gloves. This was (as far as we can tell from the investigation done by C&E News) only the second time she had used this material – certainly not a case of overly familiarity.

My personal theory is that Sheri treated the larger scale reaction as she had her previous experiment. She figured that she could just use a syringe to deliver the t-BuLi to the reaction, as she had done before. OK, it would take several aliquots, but that would not be a problem. It would save her having to use a cannula and pressure to push the reagent into another flask. I expect the first aliquot went relatively smoothly, but when she went to do that again, the syringe plunger became more difficult to pull out, then it gave suddenly and pulled all the way out.

This is often an issue when scaling up a reaction. What works on with only a small amount suddenly does not work with a much larger amount. The slightly warm reaction on 10 mL scale becomes a spontaneous reflux on 100 mL scale. The reaction suddenly doesn’t stir so well. Or, as in this case, the volume of reagents overwhelms the way that you have to deliver it.

I think I am personally so interested in this story because it is, to coin a phrase, happening where I live, that is in the laboratory, doing reactions and using potentially dangerous reagents. I can almost imagine the thought processes of the young chemist, as she tries to deal with the unfolding situation. You do not make good decisions when you are trying to improvize, you jury-rig and make do. Only by looking at the procedure before entering the lab and thinking “what is the best way to do this?” and “what can go wrong?” and “what will I do if it does?” can chemistry be safely be done, without needless loss of young lives.

Job Search Update – I Found One!

It has been a while since I gave any update on how my own job search has been going. So here is the short version:

I found a job and start next week.

The slightly longer version:

I interviewed for a position at RTI International last week. I thought the interview went well, but you are never quite sure and who knows who else is being interviewed. But anyway, after a few anxious days of almost patient waiting, I talked to my recruiter contact. She told me that a decision was pending. She called back not 30 minutes later and offered me the position. I was delighted to accept.

The position is a one year contract initially. The funding comes from a grant and this one is expected to extend that period to two years. Beyond that, further grant funding will be required, either from applications submitted by my boss or myself. In any case, I was given the opportunity to make this a long term relationship, which I hope will work out very well for all concerned.

I’m going to be enjoying my week off (a true week off!), though I plan to blog about my transition before I start work next week. And I hope to continue the blog beyond that, though I expect my new role will shape how it evolves.

Hopes and Setbacks in Alzheimers

The degeneration of patients with Alzheimer’s Disease is a tragic progression, robbing those that love them of the very essence of the personality they knew. And to this day there is no effective treatment for the disease, with a handful of drugs in use to slow down the progression. But there is no halting it – not yet.

One of the major difficulties is one of early diagnosis: by the time people realize there is a problem, the disease is already quite advanced. It is all too easy to overlook little lapses of memory and much more desirable to believe they are nothing important. Most of the time, they really are nothing – until they are not.

Some research from Duke University has given some optimism that there may be a more reliable way to predict whether someone is likely to suffer from the disease. Dr. Allen Roses had previously discovered that patients with a gene called ApoE4 that have an unusually large chance of developing Alzheimer’s, although no one had yet been able to find an effective treatment that capitalizes on this finding. Furthermore, it did not explain why patients with the more common ApoE3 gene also developed the disease. His more recent finding looks at a gene associated with the ApoE gene called TOMM40 and that there were characteristics of that gene that tallied with the progression of Alzheimer’s. The group at Duke is cautioning that this is a preliminary finding that needs to be duplicated in other laboratories. But if it is true then it will be an exciting and fruitful area of research.

This good news was welcome because another highly anticipated study gave only bad news. Glaxo’s diabetes drug Avandia failed to show any effectiveness in a clinical study. The loss of a potential $300 million for Glaxo was in itself bad news for them, but it is a setback for the theory that Alzheimer’s is a form of diabetes in the brain. This theory has had several successful studies outside of the clinic, but the Avandia study was the first to put it to the test with patients, where it was hoped that it would be able to regulate blood sugar levels in the brain, just as it does in the blood of diabetic patients. However, though the study was safe, it did not show the desired effect, adding only a few points to the cognitive scores and most effective in patients that did not carry the ApoE4 gene that is so strongly linked to the disease.

Clearly, it is not the end of this approach. There are many subtle reasons that Avandia might not have succeeded, from insufficient drug crossing the blood-brain barrier to a difference in the way that sugar is regulated in the brain. (Avandia works differently to many diabetes treatments by helping the insulin in the body to work more efficiently). It is unfortunate that it did not show at least some effect to give the other related compounds hope though, at a time that companies will be weighing the risk and benefit of funding expensive clinical studies.

At least some compounds will continue to be studied. One example comes from the Mount Sinai School of Medicine, who have studied the cognitive effect of a diabetic treatment called NIC5-15. The company manufacturing the compound, Humanetics, sponsored the study and there is an interview with their CEO here.

It is clear there is still a difficult road ahead for companies hoping to treat this terrible affliction, but the growing need for an effective treatment is a excellent stimulant to innovation and that the research is now getting at the heart of the problem has to be seen as an encouraging sign.

Update: In the Pipeline blogged on this subject, looking at the failure to show efficacy by a number of compounds.