Biology Reference
In-Depth Information
accompanied by substantial adverse effects (AEs), its use anticipated efficacy in
several diseases which are currently treated by selective PDE inhibitors or will be in
the near future. After identification of PDEs and theophylline as a PDE inhibitor in
1958, it took nearly 20 years before the clinical potential of new PDE inhibitors was
recognised. Thus, development of new PDE inhibitor drugs started at the time when
the classical drug discovery process, which was an intimate interplay between pairs
of laboratories from medicinal chemistry and pharmacology, was revolutionised by
biochemists who introduced new methodologies employing purified enzymes,
receptors or cells. The success of drug research programs depended on the under-
standing of PDEs, which appeared to be peculiarly complex due to the explosion
from originally one enzyme in 1958 to over five isoenzymes in 1985, to a protein
superfamily that is now known to contain more than 100 members. Since members
of the PDE superfamily are expressed in most, if not all, tissues, each desired effect
is potentially accompanied by other undesired side effects. In order to analyse and
discriminate between desired and adverse effects, a broad understanding of PDE
distribution needed to be established. In this historical overview, we concentrate on
PDE3, PDE4 and PDE5, where certain inhibitors are approaching or have already
reached the goal of approval for use as medications.
2 The Ancestor Theophylline: A Multitalent with Bad
Character
2.1 Asthma and Caffeine
Therapeutic efficacy of caffeine in asthma patients was originally observed and
meticulously described in 1860 by the American physician Henry Hyde Salter in his
topic “On asthma, its pathology and treatment” (Salter
1860
; Persson
1985
). Salter
suffered from asthma himself and this intimate relationship to the disease resulted
in precise observations and quite modern conclusions. He observed that bronchos-
pasms may be induced either by exercise and cold air or by the emanations of
domestic cats or hay. He thus characterised hyperreponsiveness as “excessive
irritability” of the airways in a lung of “perfect organic health”. He discriminated
these acutely occurring phases of dyspnea from more chronic airway disease, which
occur as a consequence of bronchitis or of cardiac failure (“cardiac asthma”).
He further realised that bronchospasms could be diminished by “sudden alarm,
fright, surprise or pleasant excitement” (an effect that is replicated by ß-mimetics),
smoking dried leaves of
Dattura stramonium
(which contains anti-cholinergics that
mimic atropine) or by “two morning cups of strong coffee” (which contains a mix
of xanthines corresponding to a dose of ~300 mg theophylline (May
1974
). In view
of today's knowledge, it seems that Salter's observations might have been sufficient
for the development of various asthma and/or chronic obstructive pulmonary
disorder (COPD) therapeutics as they exist today. However, systematic chemistry
and pharmacological protocols to develop such drugs for medicinal uses had yet to
be developed.
