Phosphodiesterase Inhibitors: History of Pharmacology - Phosphodiesterases as Drug Targets - page 1

Phosphodiesterase Inhibitors: History
of Pharmacology

Christian Schudt, Armin Hatzelmann, Rolf Beume, and Hermann Tenor

Contents

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

2 The Ancestor Theophylline: A Multitalent with Bad Character . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

2.1 Asthma and Caffeine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.2 Xanthines for Medical Remedies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
2.3 Rationale for Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.4 Narrow Therapeutic Window . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.5 Theophylline as Tool for PDE Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

3 Pharmacological Models Need to Be Analysed Biochemically . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

3.1 Different Inhibitory Profile Indicate Multiple Enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
3.2 Column Chromatography Profiles of PDEs and Development
of the First Generation of PDE Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
3.3 Six Lessons About PDE Inhibitor Function in Isolated Organs . . . . . . . . . . . . . . . . . . . . . . 12

4 Isolated Cellular Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

4.1 Human Platelets Offer Easy Determination of PDE3 and PDE5 Inhibitors . . . . . . . . . . 16
4.2 The PDE4-Regulated Inflammatory Cells: Neutrophils, Eosinophils,
Basophils, Monocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
4.3 T-Cells, Macrophages and Dendritic cells for Dual PDE Inhibitors . . . . . . . . . . . . . . . . . 18
4.4 Does Exposure of Inflammatory Cells to ß-Mimetics Evoke Hyperreactivity? . . . . . . 19
4.5 Correlation Diagrams: How Do Biochemical Data Correspond
to Pharmacological Results? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

5 The Path to the Clinic with Cardiovascular Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

5.1 New Drugs with PDE Inhibitor Function for Cardiac Rejuvenation . . . . . . . . . . . . . . . . . 22
5.2 Potentiating NO Action with PDE5 Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

C. Schudt ( * )
Department of Biologics, Nycomed GmbH, 78467, Konstanz, Germany
e-mail: [e-mail], [e-mail]
A. Hatzelmann, R. Beume, and H. Tenor
Nycomed GmbH, 78467, Konstanz, Germany