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 162

excellent bioavailability and a rapid T max ( o 1 h), although the estimated
clearance is slightly lower than predicted (Cl blood E 2-3mLmin 1 kg 1 ), which

results in a somewhat longer half-life of 8-12 h (initial elimination phase).
UK-390957 was progressed to Phase II studies for the treatment of PE and
showed some ecacy in PE sufferers. It was not progressed further, however,
and so its effectiveness as a treatment for PE in comparison to daily treatment
with marketed SSRI antidepressants was not confirmed.

7.5 Profile of Dapoxetine
While UK-390957 was not taken beyond Phase II by Pfizer, Johnson and
Johnson have progressed dapoxetine 71 (Figure 7.11) to Phase III studies for
the treatment of PE. Dapoxetine is an SSRI that was originally discovered by
workers at Eli Lilly in the late 1980s and progressed as a potential anti-
depressant. 33 Subsequently it was recognised that, due to its short half-life
(1.5 h) and relatively rapid T max ( 1 h), it had potential to be taken forward as

an on-demand agent for the treatment of PE. 34,35 As with UK-390957, the more
rapid T max of dapoxetine is almost certainly driven by its low V D (2.1 L kg 1 )
relative to the marketed SSRIs. In terms of lipophilicity, dapoxetine is very
similar to the marketed SSRI antidepressants and significantly more lipophilic
than UK-390957 (clog P 5.3 vs. 2.8), and yet, despite this, dapoxetine has a very
low V D , like UK-390957 and unlike the other marketed SSRIs. This clearly
shows that while lipophilicity does play a role in determining V D , other poorly
understood structural features sometimes play an even greater role.
As a consequence of its high lipophilicity, dapoxetine has very high plasma
protein binding (99% bound), which is probably important in enabling it to
maintain reasonable bioavailability (42%) by protecting it against extensive
first-pass metabolism in the liver. 34 The major metabolite of dapoxetine in vivo
is the inactive N-oxide, with the active N-demethyl analogue only being present
at low levels, 35

B

so as with UK-390957, there is no major circulating active

metabolite.
The development of dapoxetine has stimulated some debate as to whether a
rapid onset, short half-life agent is the correct approach to treating PE. While it
was proposed that on-demand dosing may be a preferred dosing regime for
patients, recent studies indicate that patients actually prefer a daily treatment

Human PK
V D = 2.1 L/kg
Plasma protein binding = 99%
F = 42%
T 1/2 = 1.5 h
T max ~ 1 h

NMe 2

SRI IC 50 = 8 nM

O

71

Figure 7.11