Major step forward in developing ‘real’ pharmacological cognitive enhancers

Co-crystal structure of a representative methoxyphenyl allosteric modulator (D159153) bound to PDE4D

The prospect that drugs might be able to enhance one or more modalities of cognition has garnered a great deal of attention in the past few years, nowhere more so than among neuroethicists.  Much of the discussion revolves around existing drugs such as methylphenidate, but the truth is that the effects they produce are measurable but modest, and in my view the current situation is not as dire as some might suggest. That might not be the case in the future, especially once ‘real’ pharmacological cognitive enhancers are developed.  To date, the results have been disappointing.  [Warning: the rest of this post is weighted more towards science than neuroethics.]

The development of ampakines by Cortex Pharmaceuticals looked promising at first, with preliminary results suggesting that these compounds might improve at least some aspects of memory in humans, but then the drugs failed to reach their end point in Phase II clinical trials.  A great deal of excitement emerged from the idea that one might be able to enhance the activity of the transcription factor CREB, primarily by inhibiting the enzyme phosphodiesterase-4 (PDE4) which is responsible for breakdown of cAMP.  If successful, the increase in CREB activity was hypothesized to enhance long-term memory.  The prominent players in PDE4 development for cognitive enhancement to date have been Memory Pharmaceuticals and Helicon Pharmaceuticals;  both companies developed drugs which advanced to Phase II testing for age-associated memory impairment, but neither drug met the requisite endpoint at moderate doses, and at higher doses ran into troublesome side effects such as nausea which have begun to be seen as a general problem with PDE4 inhibitors.

But a good idea does not lay fallow long, and a new report in Nature Biotechnology from Alex Burgin and colleagues at deCODE biostructures opens up a new era in the pursuit of PDE4 inhibitors for cognitive enhancement.  The paper is a tour de force of structural biology and medicinal chemistry.  Essentially, Burgin et al. noticed that all previous attempts to develop PDE4 inhibitors were based on developing competitive inhibitors.  Reasoning that these compounds may have been more hammer than scalpel, they used insights from their crystallography work to design allosteric modulators which might allow better titration of the cAMP signal and presumably allow fine tuning of CREB activity.  Using this strategy they ultimately came up with 140 compounds that satisfied their criteria; the most promising of these were then demonstrated to the desired effects upon long-term memory and have many of the characteristics one might wish for in a bona fide cognitive enhancer.

Effects of PDE4 inhibitors on scopolomine-induced Y-maze test (left) and novel object recognition test (right).

Most importantly, Burgin et al. went on to show that not only were their compounds effective in a few (preliminary) tests of memory, but the same compounds do not cause emesis in the Asian house shrews, beagle dogs, or cynomolgus monkeys, suggesting that they have indeed finessed the chemistry to achieve their desired aims.  In a fairly breathless commentary accompanying the paper, Miles Housley and David Adams put the findings into perspective:

Despite huge investment from the pharmaceutical industry over the last decade and extremely promising preclinical data, clinical deployment of current generations of PDE4 inhibitors has been severely compromised by nausea and emesis side-effects, which limit the effective therapeutic window. On the basis of the proposal that the emesis side effect is related to brain PDE4D inhibition, the recent focus of endeavour has been to generate compounds that show reduced inhibition towards PDE4D compared with other PDE4 sub-families in the hope of reducing emesis. Burgin et al. debunk this notion. Indeed, exploiting their structural insights, they actually set out to make highly PDE4D-selective inhibitors. Intriguingly, their lead compounds not only were brain-penetrant, and so potentially can access the emesis centre in the area postrema, but actually exhibited a greatly reduced emesis propensity coupled with excellent cognition-enhancing properties. With these results the authors chart a course for developing safer PDE4-selective inhibitors.

For long-term watchers of the pharmacological development of cognitive enhancement, the results are deeply impressive. Yes, it is a long way from demonstrating safety and efficacy in animal models to developing a drug that safely enhances cognition in normal people.  But the quality of the science and the deep insights that it brings regarding the development of PDE4 inhibitors suggests that whether or not the current group of compounds makes it through the development pathway, the field of cognitive enhancement has taken a major step forward.

There is an ironic bit of biotech company trivia at play here as well.  deCODE biostructures was a subsidiary of deCODE genetics, the top notch (and sometimes controversial) Icelandic gene sequencing company that declared bankruptcy on 11 November 2009.  Two days later, deCODE biostructures was sold to a group of investors for a very modest sum, and has reverted to its original name of Emerald BioStructures.  The paper was accepted for publication on 4 December.

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