A Case History on the Challenges of Central Nervous System and Dual Pharmacology Drug Discovery - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 268

RO

NHMe

S

NH 2

O

NMe 2

OH

Et

N O

Et

4

1 R = Me
2

3

R = H

Figure 12.1

Structures of marketed SNRIs.

12.1.1 Disease Background
Stress urinary incontinence (SUI) is the loss of urine coincident with an increase
in intra-abdominal pressure on the bladder that exceeds the urethral resistance.
Examples of triggers of involuntary leakage of urine are coughing, sneezing,
laughing and physical exercise. The dominant risk factor for SUI is gender,
with women representing over 90% of sufferers. Women are vulnerable to SUI
due to experiencing changes in their lower urinary tract anatomy during
pregnancy, childbirth and menopause. Additional risk factors are age and
obesity. Urinary incontinence tends to be regarded as an embarrassing illness
and is accepted as part of motherhood and/or aging. There are believed to be 13
million sufferers of SUI in the US and very few seek treatment. 15 People
aicted with SUI typically experience physical disability, emotional stress and
disruption to their daily life. The most widely adopted approaches to SUI are
maintenance of the condition through incontinence pads and rehabilitation
through training of the pelvic floor muscles. Surgical procedures are an option
once other approaches have failed and involve elevation of the bladder above
the pelvic floor or introduction of slings to provide additional support for the
urethra. Until recently, there were no pharmacotherapies licensed for SUI and
treatment was limited to the off-label use of non-selective a-adrenergic agonists
(improve urethral tone), tricyclic antidepressants (improve urethral tone),
b-adrenergic agonists (bladder relaxant) and estrogens (reverse atrophy). 16
In 2004, Eli Lilly introduced the dual SNRI duloxetine as the first licensed drug
therapy specifically for the treatment of moderate to severe SUI. 5

12.1.2 Target Background
The neurotransmitter 5-HT mediates its effects through at least 14 different
receptor subtypes that have been classified into seven major families,
5-HT 1 7 . 17 In a similar manner, the neurotransmitter NA acts through the a 1 -,
a 2 - and b-adrenoceptors. 18 The release of 5-HT and NA into the synaptic cleft
results in receptor activation followed by reuptake of the neurotransmitters by
their respective transporter proteins. Inhibition of these transporters with a
dual SNRI prolongs the action of the 5-HT and NA in the synapse. Selectivity