The Discovery of UK-390957: the Challenge of Targeting a Short Half-life, Rapid T SSRI - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 143

interpersonal diculty . . . ''. Although there are several plausible physiological
factors (e.g. anxiety), which may cause both lifelong and acquired PE, no psy-
chological profile or psychosocial feature is either consistent or pervasive.
Several studies have investigated the use of the marketed SSRI anti-
depressants for the off-label treatment of PE. In the clinical data that has been
published, fluoxetine 1, paroxetine 2, sertraline 3 and citalopram 4 all appear to
be well tolerated and effective, with paroxetine often being reported as the most
effective. 2-4 Fluvoxamine 5 has also been investigated but did not show effects
that were significantly different to placebo.

NHMe

F

NHMe

O

F 3 C

HN

1

O

O

3

2

Cl

O

F

Cl

O

N NH 2

NMe 2

OMe

O

5

4 F 3 C

NC

7.2 Targeting a Rapid T max , Short Half-life Agent
While the marketed SSRIs are clearly effective treatments for PE, it was
recognised that there was an opportunity to develop a rapid-onset, short half-
life SSRI for the treatment of premature ejaculation and other conditions
where on-demand (prn) dosing might be a preferred option. The antidepressant
activity of SSRIs is only evident after several weeks of chronic dosing, involving
continual exposure to free drug, as it is believed that desensitisation of 5-HT 1A ,
and possibly also 5-HT 1B , autoreceptors is required for sustained increase of
central serotonin (5-HT) levels. 8,9 On-demand dosing with a short half-life
agent would not be expected to cause this desensitisation and would not
therefore be expected to cause an antidepressant effect. On-demand dosing with
a short half-life agent would also minimise exposure to the drug and so could
result in an improved side-effect profile.
Encouragingly, just after the project to discover a rapid-onset, short half-life
SSRI had started, support for the concept of on-demand dosing of SSRIs was
provided by the report, from McMahon and Touma, that paroxetine was an
effective treatment for PE when taken as needed, 3-4 hours prior to anticipated
intercourse, in a single-blind, placebo-controlled crossover study. 10
The marketed SSRI antidepressants lack suitability for on-demand dosing as
they are lipophilic amines (pK a E

9) with high volumes of distribution (V D )