Biology Reference
In-Depth Information
acute myeloid leukaemia or B-cell lymphoma, osteoporosis, type II diabetes,
depression, schizophrenia, psoriasis and atopic dermatitis to name a few where
results from clinics or animal models have been provided. However, a higher degree
of PDE4 inhibition than tolerable with the current concept of competitive PDE4
inhibitors may be required to address some of the above mentioned conditions with
an oral PDE4 inhibitor. Only recently by researcher's at Decode (see chapter by M.
E. Gurney et al., this volume) introduced allosteric PDE4D modulators, that dually
dock to the catalytic centre and the UCR2 N-terminal region. Strikingly, opposite to
rolipram, these allosteric PDE4D modulators showed a very favourable ratio
between pharmacological efficacy in mouse models of cognition and a well-
accepted correlate of emesis in this species (Burgin et al.
2010
). The future will
show whether allosteric PDE4 modulators may further advance the tale of PDE4
inhibitors as their next generation with an even improved efficacy and tolerability.
7 Summary and Outlook
In this historical overview we recall how serendipitous findings in the clinics
discovered the therapeutical potential of natural compounds later identified as
PDE inhibitors. The progress and stepwise understanding of the dimensions
of the PDE superfamily, the isoenzymes tissue distribution, their function and
inhibition with growing selectivity was redrawn. From the PDE1-5 families the
history of PDE3, 4 and 5 was discussed in more detail since specific inhibitors have
either already reached the shelf of the pharmacist or will be launched in near future.
For PDE1 and PDE6 no specific inhibitors have been developed until now, and in
case of PDE6 it does not seem prudent to interfere with the function of this enzyme
family which is essential for perception of light by retinal photoreceptors. Devel-
opment of PDE2 inhibitors for use in treatment of CNS maladies and sepsis are
progressing and will be discussed in two subsequent chapters in this volume (see
chapter by J. Surapisitchat and J. Beavo and the chapter by Y.Liu, et al.). Regarding
PDE7-11, many ongoing research activities also in the pharmaceutical industry are
noted but any therapeutic activity has to be proven in the future. PDE4 inhibition
and its broad clinical potential justified a detailed description not only due to the
author's personal engagement and dedication, but also because this development
describes the inherent difficulties arising from obstinate adverse effects that needed
to be discriminated by drug optimisation. The first quotation of Ro 20-1724
(Hamilton
1972
) and Schering's rolipram (ZK 62-711), (Hedqvist et al.
1978
)
potent and selective PDE4 inhibitors, in the literature dates back to 1972 and
1978 and both compounds were in clinical studies. In 2010 once daily, oral
roflumilast as the first PDE4 inhibitor received market authorisation. The path to
the first PDE4 inhibitor was never simple; rather it was very difficult, required
perseverance and a conviction of “
per aspera ad astra
”. And “
asperae
” were plenty
from the early emesis problems, the problems experienced due to the existence of
