Biology Reference
In-Depth Information
efficacy. For the PDE4 inhibitors discussed (rolipram (1), ibudilast (2), tetomilast
(3), cilomilast (4), oglemilast (5), roflumilast (6), and apremilast (7); Fig.
1
), a very
brief summary of cellular, animal, and clinical findings will be added.
2 Pharmacology and Clinical Experience
2.1 Rolipram
The arylpyrrolidinone rolipram (1) was among the first discovered set of highly
selective PDE4 inhibitors. This compound was investigated in clinical development
for the treatment of depression (Zeller et al.
1984
; Laux et al.
1988
; Fleischhacker
et al.
1992
). Rolipram readily crosses the blood-brain barrier and has been found to
improve neurotransmission in central noradrenergic neurons. This observation may
account for the compound's antidepressive effects. Although modest antidepressive
efficacy for rolipram was reported in clinical settings, the extent of nausea and
vomiting caused further development to be abandoned. As the archetype PDE4
inhibitor with a rather acceptable pharmacokinetic profile in rats or mice following
i.p. or p.o. administration, rolipram excelled as a tool compound for characterizing
the putative potential of PDE4 inhibitors in countless disease-relevant cellular and
animal models but also to sharpen insights into the nature of PDE4-related adverse
effects such as nausea and vomiting.
On the basis of promising results to alleviate symptoms in experimental autoim-
mune encephalomyelitis (EAE) rodent models, the effects of rolipramwere explored
in a very small number of patients afflicted with multiple sclerosis. Although
rolipram (maximal dose of 9 mg per day) exerted inhibitory effects on peripheral
blood mononuclear cells, the primary outcome measure (contrast-enhanced lesions
in magnetic resonance imaging (MRI) reflecting blood-brain barrier disruption
secondary to brain inflammatory activity) worsened rather than improved. Along
with poor tolerability, this finding accounted for premature termination of that study
(Bielekova et al.
2009
). The reasons for the enhanced brain inflammatory activity
with rolipram are not entirely clear; however, one may consider that not only TH1
cells but also other T-cell subpopulations such as TH17 cells are now considered
being critical orchestrators in multiple sclerosis. Authors indicated the study does
not exclude that PDE4 inhibitors may exert neuroprotective or immunomodulatory
effects independently of blood-brain barrier disruption. In any case, caution should
be taken in investigations with PDE4 inhibitors in multiple sclerosis.
2.2
Ibudilast
Ibudilast, a pyrazolopyridine (2, Kyorin Pharmaceuticals), may be at best consid-
ered as a weak, mixed type PDE4, PDE10, and PDE3 inhibitor with IC
50
in the low
micromolar range and little specificity for PDE4 (Gibson et al.
2006
; Huang et al.
