Phosphodiesterase Inhibitors: History of Pharmacology - Phosphodiesterases as Drug Targets - page 4

Table 1 Clinical studies with prototypical PDE inhibitors
Inhibitor PDE Indication Assessment References

Theophylline Unsel Asthma, COPD Symptoms Hirsch ( 1922 )

Amrinone 3 Chronic heart failure Myocardial

contractility

Benotti et al. (1978)

Enoximone 3 Pulmonary

hypertension,
COPD

PAH, bronchodilation Leeman et al. ( 1987 )

Rolipram 4 Depression Depression scale Horowski et al. (1985)

Ro 20-1724 4 Psoriasis Disease score Stawiski et al. ( 1979 )

Denbufylline 4 Multi-infarct

dementia

Psychometry O'Connolly et al. ( 1988 )

Zaprinast 5 Exercise-induced

asthma

FEV1 during exercise Rudd et al. ( 1983 )

Zardaverine 3/4 Asthma FEV1 Brunn´e et al. (1992)

Papaverine Unsel Erectile dysfunction Penile erection Brindley ( 1982 )

Benafentrine 3/4 Bronchoconstriction

in volunteers

Methacholine-induced
FEV1decrease

Foster et al. ( 1992 )

Tolafentrine 3/4 Pulmonary

hypertension

PAH Ghofrani et al. (2002b)

Sildenafil 5 Erectile dysfunction Penile erection Boolell et al. ( 1996 )

Pulmonary
hypertension

PAH, exercise
tolerance

Ghofrani et al. ( 2002a )

Cilostazol 3 Intermittent

claudication

Walking distance Kumar et al. (2007)

Piclamilast 4 Rheumatoid arthritis Disease score Chikanza et al. ( 1996 )

Cilomilast 4 COPD FEV1 Compton et al. ( 2001 )

Roflumilast 4 COPD FEV1, acute

exacerbations

Calverley et al. (2009)

Clinical studies are listed which have been performed with prototypical, advanced and “first-in
class” PDE inhibitors. Theophylline and papaverine are denominated as unselective (unsel) PDE
inhibitors

of these procedures were established, and high throughput screens testing more
than 10,000 compounds per day were the pride of every scientific board. The role
of classical pharmacology was now to compare compounds preselected by bio-
chemical methods and to characterise candidates with regard to (1) in vivo potency,
(2) duration of action, (3) efficacy and (4) adverse effects. In view of the change in
the approach of drug development to specific (enzyme) targets, PDE research was
a latecomer due to the continuous discovery process of multiple PDE activities
and the insufficient insight into relationship between PDE subtypes and pathologi-
cal functions. However, as the complexities of the PDE superfamily were slowly
defined and isolated PDEs became available for study, a greater understanding of
their function emerged.
A history of the pharmacology for drugs that inhibit PDE needs to start with the
role of the ancient PDE inhibitor theophylline, which was in use therapeutically
long before its biochemical action was characterised in 1958. Independently of its
biochemical function, theophylline stimulated myriads of pharmacological inves-
tigations. Its clinical use followed the pharmacological studies, and despite being