Biology Reference
In-Depth Information
the three essentials (1) the disease indication, (2) the chemical compounds which
should be examined or derivatised and (3) the armamentarium of models which
were available and could be used for the intended project.
The clinical indications needed to be (1) painful, (2) life-threatening and (3)
“ethical”. The pharmacological models had to be designed to deliver read-outs
for (1) therapeutical efficacy, (2) dosage and (3) side effects. These parameters
were evaluated in anaesthetised intact animals suitable for measuring respiration
and cardiovascular and metabolic parameters. Efficacy and potency of various
compounds were compared and quantified in isolated organ preparations. These
models detected either contractions or relaxations of muscle preparations that had
been developed since the beginning of the twentieth century. They provided
dose-response curves, were independent from the whole organism and contributed
essentially to the selection of new chemical entities (NCEs), which for patent and
commercial reasons needed to show “significant advantage and progress” over
existing medications.
Most problematic was the source of chemicals used for investigations. The
available compound sources were (1) antagonists (of or toward) hormones and
mediators, (2) alkaloids which were highly effective but tremendously toxic and (3)
some heterocyclic compounds which were used as diuretics, antihypertensives,
cardiotonics, pain killers or anti-infectives. Each new project had to be initiated
with a long and careful search in the chemical literature for identification of
structures which might eventually be active in the biological system of question.
The yield, however, was usually low, and even in the middle of 1970, most new
developments were called “me-too” compounds developed on the basis of already
existing, less effective drugs. After performing toxicologic testing, these substances
could eventually be administered to humans. The important tasks of pharmacology
were to (1) provide evidence for efficacy and proof of concept in vivo, (2) identify a
relevant dose in combination with pharmacokinetics and (3) define a safe “first dose
in man”. Elucidation of the mechanism of action (MoA) was desirable but not
considered to really be necessary. The area of phosphodiesterase (PDE) inhibitor
provides several examples for this fast track path to clinical application in the
period from 1977 to 1985 (summarised in Table
1
).
In the years between 1950 and 1970, basic biochemical research was successful
in isolating many enzymes and clarifying their functions, identifying key enzymes
of metabolism and starting to analyse molecular mechanisms of diseases. Examples
for pioneering research with prominent key enzymes, which were snatched up by
pharmaceutical industrial laboratories, were HMG-CoA reductase for cholesterol
synthesis, angiotensin-converting enzyme (ACE) for regulation of blood pressure,
xanthine oxidase for gout and Na/K-ATPase and the H/K-ATPase for gastric acid
secretion. These drug targets were established with considerable success in the
years between 1970 and 1980. Enzymes and isolated cells - primary and immorta-
lised - provided a completely new armamentarium for use in pharmacological
research. About 10- to 100-fold more measurements per day became possible and
identification of true new lead structures from the pool of stored chemicals in each
company became a real possibility. Beginning in 1990, highly automated versions
