Biology Reference
In-Depth Information
may propose the idea that the rather smooth pharmacokinetic profile, specifically
the lack of sharp
C
max
peaks obtained following repeated dosing of roflumilast in
humans, contributes to its favorable tolerability versus earlier PDE4 inhibitors
such as rolipram. In this respect, pharmacokinetics is one important determinant
of overall efficacy versus side effects, in addition to the ratio of the inhibition
of fMLP-stimulated superoxide release from neutrophils (80% plasma) versus LPS-
induced TNF-
a
release in human whole blood as discussed before.
The discussions above are based on many extrapolations from plasma levels to
cellular effects (and even those in humans), which certainly have their limitations.
For example, concentrations of compounds at the target cells remain unknown.
They may perhaps be close to those in the plasma, but there are no studies proving
this concept in detail. Results of the in vitro cellular assays with whole blood or
plasma may vary with different experimental conditions or stimulus concentrations.
Notwithstanding this, one interesting observation remains that the two compounds,
which perhaps most convincingly showed clinical efficacy (roflumilast and apre-
milast), are among those with clinical plasma levels corresponding to substantial
inhibition of PDE4 and cellular functions.
On the basis of cellular and specifically animal studies, the therapeutic potential
of PDE4 inhibitors may be wide ranging from COPD and asthma to idiopathic
pulmonary fibrosis, inflammatory bowel disease, psoriasis, and atopic dermatitis,
then rheumatoid arthritis, osteoporosis to B-cell chronic lymphocytic leukemia
(B-CLL), acute promyelocytic leukemia, and even Alzheimer's and cognitive
deficits to name but a few. What could be the strategies for design of PDE4
inhibitors with an even improved therapeutic index compared with those that
currently are rather promising?
One strategy may be topical administration when possible, such as for respira-
tory or skin disorders, by designing compounds with a high local, yet very limited,
systemic exposure, mostly based on physical chemistry and pharmacokinetic
optimization. As some of the ailments with prominent local manifestations bear
critical systemic components (such as in COPD or psoriasis), these approaches may
eventually reveal to be of limited potential as based on their design the compounds
may not address these systemic components of the disorder.
Another strategy that was exploited for cilomilast, and perhaps tetomilast,
has been to design compounds that based on their pKa are cationic or anionic at
physiological pH. These charged species may be expected to bear low passive
penetration over the blood-brain barrier to limit CNS-related adverse events.
However, this approach may not reduce the appearance of emesis because the
area postrema is located outside the blood-brain barrier. In addition, as observed
with cilomilast and tetomilast, compounds being anionic at physiological pH may
show a high plasma protein binding.
A third approach has been to generate PDE4B-selective compounds, following
the optimism generated by results from the PDE4B- versus PDE4D-deficient mice
that PDE4B accounts for many anti-inflammatory effects, whereas PDE4D may be
related to emesis. While generating subtype selectivity for PDE4B appears a
challenging endeavor for the medicinal chemist, over the past few years, evidence
