Neurochem Res (2014) 39:1847–1849
DOI 10.1007/s11064-014-1437-5
COMMENTARY
Povl Krogsgaard-Larsen: A Giant in Medicinal Chemistry
Research
Klaus P. Bøgesø
Published online: 18 September 2014
 Springer Science+Business Media New York 2014
Povl Krogsgaard-Larsen is a true giant in medicinal
chemistry and without doubt the person that has had the
greatest impact on this discipline in Denmark.
I got to know Povl in the spring of 1970. After I had
finished my chemical engineer education, I had to serve
20 months in the Danish Civil Defense corpse. The last
10 months were spent at The Royal Danish School of
Pharmacy (at that time this was an independent university,
today it is School of Pharmaceutical Sciences at Faculty of
Health and Medical Sciences, University of Copenhagen)
in The Civil Defense analytical laboratory. Povl was doing
his PhD project during that period and his lab was in the
same building. We met during coffee breaks, symposia,
etc. After finishing my service in the Civil Defense corpse,
I started as a medicinal chemist at the Danish pharma-
ceutical company H. Lundbeck A/S. Lundbeck was known
for its antipsychotic and antidepressant drugs, and I quickly
became involved in research projects aiming at discovering
new, improved drugs within these classes. However, I kept
a close connection to Povl and, as described below, we
have over the years collaborated on a number of different
projects and topics.
Povl first became interested in the inhibitory neuro-
transmitter c-aminobutyric acid (GABA) and, during the
next decade, he and his group designed a large number of
compounds to map the structure–activity relationships
Special Issue: In honor of Krogsgaard-Larsen.
This is a commentary article to the Preface article DOI 10.1007/
s11064-014-1408-x.
K. P. Bøgesø (&)
R&D External Affairs, H. Lundbeck A/S, Ottiliavej 7-9,
2500 Valby, Denmark
e-mail: kb@lundbeck.com
(SAR) of GABA receptors and uptake sites. This work
made the foundation of his doctoral thesis from 1980 [1].
During the following years, Povl extended his research area
to also encompass the neurotransmitters acetylcholine and
glutamic acid.
Povl’s ambition has not been to make drugs but to
explore the pharmacology and SAR of the three neuro-
transmitters mentioned above. He has done this by making
a large number of invaluable tool compounds which
facilitated not only his own research, but also the research
of hundreds of researchers all over the world to whom he
has generously donated his tools.
Nevertheless, several compounds with drug potential
have emerged over the years (the most famous example is
Gaboxadol, see below).
Povl’s strategy for handling the development of these
lead compounds has always been a trustful collaboration
with the industry, in many cases with Lundbeck. He
strongly believes that patenting and development should be
done by professionals, i.e. the industry. Many years ago,
Lundbeck made a framework agreement with Povl that
regulated such a collaboration. In essence, Lundbeck could
in-license a new project if they were interested, and the
new project and structures were added to the agreement in
an appendix. Subsequently, the parties collaborated with
further syntheses, testing, and patenting.
The keyword here is trust. For Povl, it is essential that
the collaboration is open, trustful and with respect for each
other’s expertise, and that, at any time, information can be
given without fearing that it is leaked to the outside.
This type of collaboration can be very beneficial for
both parties. For Lundbeck, it gave access to new CNS
areas where we had no previous expertise, including sub-
stantial knowledge and technology transfer. Furthermore,
through mutual PhD students and involvement in the
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education of researchers, Lundbeck got close access to new
talent when recruiting.
For Povl, it gave him the freedom to concentrate on
basic research which was further qualified by extensive
testing (especially in vivo) in industry, development of key
compounds, funding, and an insight in drug discovery and
development in industry.
Today, there is much focus on improving industry–
academia collaboration through public–private partnerships
(PPP), not only in Denmark, but all over the world. I
believe that the type of collaboration described above show
that Povl has always been ahead of his time in this respect.
Inspired by this, Lundbeck has favored this adaptive col-
laboration structure through what we call adaptive frame-
work collaboration. We have recently described this in
more detail [2].
Povl’s dedication to the academia–industry integration
is clearly seen by his strong engagement in the establish-
ment and management of a series of biotech centers at the
University over a period of more than 25 years. These
centers have been funded partly by the government, partly
by the university, and partly by industry. They have
included research schools, symposia (with funding for
external teachers and speakers), and a large number of PhD
students. The topics of the majority of the PhD projects are
defined together with an industry partner, and part of the
practical work was often done in industry with surveillance
of an industry supervisor. Industry was also represented in
the board of the center. Today, the Danish politicians call
for more and improved PPPs, but it is acknowledged that
precisely the School of Pharmaceutical Sciences is a role
model in this respect. To a large degree, this is due to
Povl’s engagement in this matter over many years.
Another example of Povl’s engagement in putting sci-
ence to work is that he has been calling to arms for an
increased focus of university researchers on Scientific
Social responsibility (SSR) [3]. He is arguing that the
concept of basic versus strategic research is artificial, not
only in an operational sense, but also in a value-for-money
perspective. This is because money allocated by politicians
to rather narrow defined ‘‘strategic’’ areas lead mostly to
incremental improvements of existing technologies. What
is needed are technological breakthrough discoveries
through dynamic and visionary ‘‘basic’’ research which
then result in a ‘‘strategic’’ output by visionary scientists
who understand SSR. SSR is defined as ‘‘…the responsi-
bility of scientists…to position and define their research
activities in a context where they are able to contribute to
the betterment of society and to help meet the Grand
Challenges of our time’’.
However, what many had not seen coming for a brilliant
scientist as Povl was that he should become an industrial
leader himself. Povl had since 1993 been a member of the
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board of Carlsberg breweries where the deed of the
Carlsberg Foundation demands that the board includes five
Professors, all being members of the Royal Danish Acad-
emy of Sciences and Letters. In 2001, he became Rector of
the Danish University of Pharmaceutical Sciences, but after
2 years in this role, he was appointed Chairman of the
Board of the Carlsberg Foundation. Also in this role which
he kept to 2012, he impressed everybody by his leadership
that also was acknowledged officially by appointing him as
Chairman of The Year in 2010. During his leadership,
Carlsberg made the biggest deal ever in Denmark by
acquiring the Scottish Brewery, Scottish & Newcastle.
Finally, a few words about Gaboxadol. This compound
is a bicyclic analogue of muscimol, a natural compound
isolated form the mushroom Amanita muscaria, and it was
synthesized already in 1973 [4]. Originally, it was named
THIP (an acronym for its chemical name 4,5,6,7-tetra-
hydroisoxazolo[5,4-c]pyridine-3-ol). THIP is a GABA
agonist which proved to be much more tolerable than
muscimol in vivo, making it a potential candidate for
clinical investigation. There was a theoretical possibility
that a GABA agonist might be useful in certain CNS dis-
eases for example schizophrenia, Huntington’s disease, and
epilepsy. Therefore, Lundbeck became interested, in
licensing the compound and started development of it.
THIP was chemically a challenge, being very different
from the antipsychotic and antidepressant compounds
Lundbeck usually worked with then. Upscaling the THIP
synthesis was a major undertaking, involving both Povl and
several Lundbeck chemists.
THIP was clinically tested in a number of small studies.
In the end, it was discovered to have an excellent analgesic
effect. Lundbeck made a co-development agreement with
the Swiss company Sandoz, but after a few years the pro-
ject was terminated due to a fast hydrolysis of the com-
pound in the intestines. However, many years later Povl
was approached by Dr Marike Lancel from the Max Planck
Institute in Munich. She had already shown the utility of
THIP as a hypnotic agent, both in animals and a small
phase I study. The very short half-life mentioned above
was ideal for a hypnotic. So Lundbeck, this time together
with MSD, developed THIP, now named Gaboxadol, for
sleep disturbances. Unfortunately, despite a good effect on
sleep, the compound failed very late in a dose response trial
on drug abusers due to psychiatric and other side-effects in
high doses [5]. It was of course a great pity, because with
this compound Povl had created a truly unique drug, a drug
with no obvious back-ups. The story has recently been
published [5].
In conclusion, Povl has been extremely influential in a
number of very different fields. When appointed Chairman
of the Year in 2010, the nomination statement describes
him as a listening, curious, and seeking soul who under
Neurochem Res (2014) 39:1847–1849
pressure show the necessary courage to make really big
decisions. This is true. For example, Povl will anytime
prefer a telephone conversation to a mail. In the conver-
sation, he will listen to arguments and explore his own
thoughts. He has an impressive memory, and his way of
keeping order of publications and records of any kind is
legendary. Furthermore, he is very polite, but has a unique
way of having his way in the end—by convincing argu-
ments. He has recently published his autobiography (in
Danish) [6]. As an example of his listening behavior, he
says in one place ‘‘I like the position as the fly on the wall’’.
In another place, he says that while he has never looked for
money, general public recognition, or outwards things, he
does appreciate to be recognized for his research. Povl has
received a long row of awards and prizes as signs of sci-
entific recognition. He is also Doctor Honoris Causa at the
Uppsala, the Milan, and the Louis Pasteur Universities.
Presently, he is on the Board of the Lundbeck Foundation
and is the Chairman of the Grete Lundbeck Brain Research
Foundation.
On the question of role models, he says he had none
because this is the conditions of the pattern breaker (his
1849
father was a farmer). I feel that a good deal of the expla-
nation of his diligence and success in many different fields
can be ascribed to this role as the pattern breaker. Con-
cerning role models, I am fortunate to actually have one:
Povl!
References
1. Krogsgaard-Larsen P (1980) Specific GABA receptor agonists and
uptake inhibitors: design, development and structure–activity
studies. FADLs Forlag, Denmark
2. Vedel JB, Irwin A, Andersen PH (2013) Externalizing research
through adaptive frameworks. Nat Rev Drug Discov 12:723–724
3. Krogsgaard-Larsen P, Thostrup P, Besenbacher F (2011) Scientific
social responsibility: a call to arms. Angew Chem Int Ed
50:10738–10740
4. Krogsgaard-Larsen P (1977) Muscimol analogues. II. Synthesis of
some bicyclic 3-isoxazolol zwitterions. Acta Chem Scand B
31:584–588
5. Morris H (2013) Gaboxadol. Harpers Mag 327:43–47
6. Bjerager A-L (2011) Bryggerens lærling. Povl Krogsgaard-Larsens
erindringer. Gyldendal, Denmark
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