Biology Reference
In-Depth Information
Table 3 Effective inhibition of PDE4 subtypes achieved in human clinical trials related to emesis
Units
Cilomilast
Roflumilast
Roflumilast
N-oxide
MW
gm/mol
343
403
419
hPDE4D7 IC
50
ng/ml
36.7
1.7
4.6
hPDE4B1 IC
50
ng/ml
122
2.9
4.3
LTE4 IC
50
ng/ml
395
2.2
13.4
TNF
a
IC
30
ng/ml
1,715.0
20.2
21.0
Clinical dose
15 mg b.i.d.
0.5 mg q.d.
C
max
ng/ml
990
3.9
8.4
AUC (0-24)
ng.h/ml
22,000
35
147
C
av
(AUC/24)
ng/ml
916.7
1.5
6.1
Occurrence of
adverse events
10% Subjects
reported nausea
Diarrhea (8%),
nausea (8%)
>
Therapeutic index Clinical
C
max
/
LTE4 IC
50
2.5
1.7
0.6
LTE4 effective
dose (
C
av
)
% Inhibition
ED70
ED39
ED31
TNF
a
effective
dose (
C
av
)
% Inhibition
ED19
ED3
ED11/ED22(ss)
Biochemical in vitro assay data (hPDE4D7, hPDE4B1) and human whole blood LTE4 production
after Sephadex-stimulation (LTE4 IC
50
) are from [(Burgin et al.
2010
) and unpublished]; data on
human whole blood TNF
a
production after LPS-stimulation are from (Hatzelmann and Schudt
2001
). Cilomilast clinical dose, pharmacokinetic data and occurrence of adverse events are from
(Giembycz
2006
) or from US FDA Docket 3976B1, Pulmonary-Allergy Drugs Advisory Com-
mittee, Preclinical Considerations, FDA, Table
1
; single dose AUC. Roflumilast clinical dose,
pharmacokinetic data and occurrence of adverse events are from (Lipworth
2005
) or Wurz W
(2002) Altana Pharma, Roflumilast, Frankfurt/Main slides 21-22.
5 UCR2-Directed Allosteric Modulators Bind an Asymmetric
PDE4 Conformer
The binding pose of UCR2-directed allosteric modulators exploits an asymmetric
PDE4 conformer in which one active site is capped by UCR2, while the second
active site remains open (Fig.
3
). Polymorphism in a key residue on UCR2, Phe196
in PDE4D and Tyr274 in PDE4B, has allowed the design of compounds that are
100-fold selective for either PDE4D (Burgin et al.
2010
) or PDE4B (unpublished).
Compounds acting allosterically to close UCR2 act as bi-dentate ligands with one
end binding UCR2 and the other binding within the active site.
Atypical PDE4 inhibitors such as rolipram, RS25344, and PMNPQ that bind to
UCR2 (Jacobitz et al.
1996
; Rocque et al.
1997
; Saldou et al.
1998
; Burgin et al.
2010
) are highly emetic (Hebenstreit et al.
1989
; Robichaud et al.
1999
,
2001
).
However, early in our studies of the structure-activity relationship (SAR) for
compounds binding to UCR2, we identified compounds that did not completely
inhibit the enzymatic activity of the PDE4 dimer due to negative cooperativity
between the two active sites.
I
max
was a maximum of 85-90%.
I
max
was decreased
