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Table 8.1 Cyclic nucleotide specificity and discovery date for PDE isoforms.
PDE subtype
Specificity
Year of discovery
1A, 1B
cGMP 4 cAMP
1970
1C
cGMP
¼
cAMP
1970
2A
cAMP 44 cGMP
1970
3A, 3B
cAMP 44 cGMP
1970
4A, 4B, 4C, 4D
cAMP 44 cGMP
1970
5A
cGMP 44 cAMP
1978
6A, 6B, 6C, 6D, 6G, 6H
cGMP 44 cAMP
1985-2000
7A
cAMP 44 cGMP
1993, 2000
8A, 8B
cAMP 44 cGMP
1998
9A
cGMP 44 cAMP
1998
10A
cGMP
¼
cAMP
1999
11A
cGMP
¼
cAMP
2000
distribution and their specificity for the cyclic nucleotides. Much of the early
work in the PDE field was carried out prior to the characterisation of the entire
PDE family; hence many early drug candidates were subsequently found to
have suboptimal selectivity.
The discovery of the potent, selective PDE5 inhibitor sildenafil enabled the
clinical investigation of the role of PDE5 in humans.
3
Since PDE5 is widely
expressed in smooth muscle throughout the body, several potential indications
have been identified for PDE inhibitors. After initial investigation as a potential
anti-anginal, the observation of spontaneous maintained erections in early
clinical trials lead to the development of sildenafil as a treatment for male
erectile dysfunction (Viagra
t
). However, further studies identified an addi-
tional utility for PDE5 inhibitors as a new treatment option for pulmonary
arterial hypertension (PAH), leading to the approval of an alternative dosage
form of sildenafil (Revatio
t
).
4
Following the disclosure of the first clinical results for sildenafil, interest in
PDE5 inhibition was stimulated industry-wide. A number of different chemo-
types were identified, but only three additional NCEs representing two che-
motypes have been approved [vardenafil,
5
tadalafil
6
and udenafil
7
(Figure 8.1)].
Each of the chemotypes can be characterised by their selectivity profile over the
other members of the PDE family. Thus the sildenafil/vardenafil/udenafil
chemotype results in high selectivity over all PDEs other than PDE6, whereas
tadalafil was found to have low selectivity over PDE 11. Inhibition of PDE6 is
thought to contribute to undesired visual side effects,
8
while PDE11 inhibition
has been implicated in spermatogenesis.
9
Ongoing clinical and pre-clinical studies with sildenafil,
10
and subsequent
clinical candidates from the same series, identified several additional indica-
tions for PDE5 inhibitors. Since these include disease indications (e.g. hyper-
tension, diabetes) requiring chronic treatment and/or single-dose daily
administration in order to be competitive, we sought novel agents with an
excellent safety profile and, in particular, no potential for off-target activity
against other PDE family members. Based on our clinical experience with
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