Biology Reference
In-Depth Information
6 New PDE Inhibitors Against Airway Diseases Without Vomiting . . . . . . . . . . . . . . . . . . . . . . . . 24
6.1 The First Goal: An Improved Bronchodilator with Anti-inflammatory Potential . . . . 24
6.2 Animal Models for Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
6.3 Zardaverine and Tolafentrine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
6.4 Early Strategies for Avoiding Nausea and Vomiting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
6.5 Animal Models for COPD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
6.6 COPD Pathomechanisms Overlap with Oral PDE4 Inhibitor Potential . . . . . . . . . . . . . . 32
7 Summary and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Abstract The first pharmacological investigations of phosphodiesterase (PDE)
inhibitors were developed with the clinical efficacies of drugs isolated from coffee,
cacao and tea but only later their relevant ingredients were identified as xanthines
that act as PDE. With its diuretic, inotropic and bronchodilating clinical efficacy,
use of theophylline anticipated the clinical goals, which were later approached with
the first-generation of weakly selective PDE inhibitors in the period from 1980 to
1990. Pharmacological and clinical research with these early compounds provided
a vast pool of information regarding desired and adverse actions - although most of
these new drugs had to be discontinued due to severe adverse effects. The pharma-
cological models for cardiac, vascular and respiratory indications were analysed for
their PDE isoenzyme profiles, and when biochemical and molecular biological
approaches expanded our knowledge of the PDE superfamily, the purified isoen-
zymes that were now available opened the door for more systematic studies of
inhibitors and for generation of highly selective isoenzyme-specific drugs. The
development of simple screening models and clinically relevant indication models
reflecting the growing knowledge about pathomechanisms of disease are sum-
marised here for today's successful application of highly selective PDE3, PDE4
and PDE5 inhibitors. The interplay of serendipitous discoveries, the establishment
of intelligent pharmacological models and the knowledge gain by research results
with new substances is reviewed. The broad efficacies of new substances in vitro,
the enormous biodiversity of the PDE isoenzyme family and the sophisticated
biochemical pharmacology enabled Viagra to be the first success story in the field
of PDE inhibitor drug development, but probably more success stories will follow.
Keywords Asthma
COPD
PDE inhibitors
PDE4 inhibitors
1
Introduction
Drug discovery up to 1970 usually happened in small research departments which
represented a minor activity of a chemical company. The research team consisted
of chemists and pharmacologists. The latter were educated as medical doctors and
thus knew the areas of urgent medical need. This team decided about the goals of
research (not the board) - mainly on the basis of available resources - and defined
