Addicted to Chemistry

Making useful agents for studying substance abuse disorders.

Leave a comment

Colorful Chemistry: Part 1

Happy Tuesday!

I thought I would share a series of photos from last week, where I had occasion to convert a pyridyl ketone into an oxime.

reaction 2

When I first added hydroxylamine hydrochloride to the flask, I noted that the clear solution immediately took on a pinkish hue. We are stirring on ice just to be safe.

After about 15 minutes, I checked back on the flask and noticed that the color had changed from pink to a dark orange, maybe the color of pulpy orange juice. You can see that at the right.reaction 3

These first two color changes both took place at temperature around 0-5C. Of course, it is not uncommon for colors to change as a reaction proceeds to product. I wondered whether this would be the color of our pyridyl oxime product; I took the reaction out of the bath, and let it stir at room temperature to complete the conversion.

reaction 4

At left is the final color change as product formed. What once was pink, then orange, now took on a salmon color; I suspect this is the result of the reaction “splitting the difference,” and having the dark orange offset by the light pink. This is all pre-workup, too, so there is aqueous HCl and triethylamine floating around in there (we went with NEt3 over pyridine to aid the workup). Pyridine is not your typical tertiary base in many respects. So, the “fireworks” that we see here is not necessarily unexpected, but it cool to note anyway.


Leave a comment

Summer has started!

Another semester down, infinite more to go. Hopefully, the future will not include (m)any more semesters like I just had (coordinator of 3 courses, teaching in a 4th, and day-to-day fires to extinguish).

With this post, we head into the summer. I have an awesome team of around 8 Pharm.D.’s and undergrads who are working on some projects with me and others in our group, in synthetic organic chemistry, molecular modeling, and also in vivo pharmacology. My fantastic technician, Rachel, just took a position at MCW, which we are also excited about.

20160603_134949To kick things off, here is a shot of our first purified product that is ready to ship out this week. We found a new set of conditions that affords us a Knoevenagel condensation, and, perhaps more crucially, we found a solvent system that lets us purify the spots shown here. That took a little luck, actually; those two spots were stubbornly on top of each other until we landed here, and crystallization/salt formation was giving us fits. Now that we have conditions down, we are ready to rock and/or roll! Keep looking here for updates.

Leave a comment

A shout-out to a startup

ALT Pharmaceuticals is a new startup out of University of Maryland, Baltimore (full disclosure: I earned my Ph.D. from there. Fuller disclosure: I worked for both Andy Coop and Alex MacKerell, both of whom are co-founders of ALT). They are working on trying to develop analgesics lacking tolerance, dependence, and abuse potential.

If this sounds familiar to you, it should: I have been working in this field for a decent amount of time. In fact, a great number of opioid chemists and pharmacologists have been trying to make a non-addictive substitute for morphine for the better part of a century. We are smart men and women, and the NIH has been pumping millions (billions?) of dollars into this over the years; so the logical question, then, is:

what the hell are we doing wrong?

The answer, like just about everything in life, is complicated: “pain” is a multifaceted disease state and has a subjective component; progression of a disease state, if inadequately treated itself, can exacerbate a painful condition; psychologic dependence, as opposed to physiologic dependence, also likely plays a sizable role. These are all things that are difficult to “tease out” from a drug design standpoint.

What we, as medicinal chemists, can do is try to counteract the mechanisms by which our bodies respond to repeated bombardment by pharmaceuticals. When our opioid receptors are chronically stimulated, they can be internalized and degraded, desensitized, and their synthesis up- or down-regulated. Where the problem lies – and this is that multi-million dollar question – is in figuring out how we can trick the brain and the body into not responding like this. Andy and Alex have models that appear to facilitate drug discovery; others of us look to re-purposing and natural products to gain inspiration. They are all valid approaches, and all ways to discover some exciting new agents that might be therapeutically useful.

Hopefully this underscores how vital it is that the NIH continues to support basic research in the substance abuse field, since there is just so much we have yet to learn about the mechanisms underlying tolerance and dependence. As the old saying goes, you can’t fix a car if you don’t know what’s broken: so, too, we may never reach that goal of a non-addicting opioid if we do not understand the mechanisms underlying the disease.

Leave a comment

So, what happened with BIA 10-2474?

It will be a long time before the world knows what happened in the recent failed Phase I clinical trial in France, but here is what we can talk about today. There is a Wikipedia page that has a bit of relevant information.

First, some background on the drug development process. This was a Phase I clinical trial, meaning the company was looking to make sure that the compound was safe when administered to a limited number of patients. Furthermore, it was a “first-in-man” (FIM) trial, which means this compound had never been dosed to patients before (this is an important distinction, because you could have a situation where a compound goes through multiple Phase I trials).

Before a Phase I trial, a company will put an advanced lead molecule through a series of animal studies, each one providing information on effectiveness, metabolism, toxicity, etc. The more studies you have, the more data you have available when you design your FIM. For example, if you find that dosing chimpanzees with 100 mg/kg causes them to start seizing, you know that this is a dose that you do not want to reach in humans. This is called “dose translation,” and is not a trivial thing to do. We will talk about this later.

What we know about this trial is that around 100 patients were exposed to BIA 10-2474 and 5-6 suffered significant adverse events after receiving multiple doses. This means most patients, specifically those who received lower doses and less often, did not suffer serious adverse effects. It also tells us that there was something about that high dose, multiple dose regimen that was catastrophic.

So what might have happened?

In the coming weeks and months, the world will learn much about the design of the study, and the preclinical data that went into it. Here are some points that I think will be raised:

  1. Translation of animal data to human data failed to properly address species differences. Humans are different from mice and chimps (duh), but we are usually able to account for that. What is/are the differences germane to this compound that regulators missed? Specifically, how well did the various species metabolize and eliminate the compound, and could a species difference be to blame for toxic levels being reached in humans?
  2. How was the target selectivity of BIA 10-2474 assessed? Since other FAAH inhibitors were safe in patients (a Pfizer compound went through Phase II trials a few years ago), it begs the question of whether this particular compound has an off-target effect that other FAAH inhibitors do not.
  3. What metabolites and degradation products are known for this compound? Imidazole-1-carboxamides are used by organic chemists to synthesize amides because of their high reactivity with nucleophiles in the presence of Lewis acid. As a medicinal chemist, I would look at that structure and be concerned (note: it is easy for me to hindsight on this, given what we know). Where I am going with this in layman’s terms is, the structure on the Wikipedia page looks to me like it would not be terribly stable in the body, or potentially in a pill or dosage form. What do those metabolites look like, and what activity do they produce at high doses?

It will be crucial to address these issues, not only to answer to the patients and families of those affected by the trial, but also to not malign an entire class of possible therapeutics because of the horrible effects of a single agent. There will be much for doctors, pharmacists, pharmacologists, and medicinal chemists to learn from this disaster.

Leave a comment

Well, this isn’t good…

Looks like there was a disaster in France in a Phase I clinical trial of a compound that is being reported as a “cannabis-based painkiller.” Yikes.

The trial appears to be run on a candidate produced by BIAL in Portugal. There is very little confirmed information out there, so I will not contribute any of my speculation to the Twitterverse.

What I can say is, if it is indeed a BIAL compound, and if it does work through a cannabinoid-type mechanism, then it is likely NOT “cannabis-based.” I ran a quick SciFinder search of BIAL-generated literature and patents, and everything I can find suggests they make a lot of FAAH inhibitors. Yes, they work on the endocannabinoid system (like a lot of safe things do!), but no, they are not based on marijuana.

Much more information is needed, and will come, but for now I offer this plea for the news media and general public to wait for more information before judgements are passed with regards to the science. I say this not only as a medicinal chemist whose research centers around neurochemical receptors and targets, but also as a concerned scientist.