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 270

with inhibitors of CYP2D6 and/or CYP1A2. 25 Duloxetine is a moderate
CYP2D6 inhibitor (in vitro IC 50 ¼ 7 mM) 26 and increases the exposure of drugs
metabolised by CYP2D6. 25 The clinical ecacy of duloxetine (40 mg bid) in the
treatment of SUI has been established in nine double-blind, placebo-controlled
studies that randomised adult women (n ¼ 3063) with symptoms of SUI. 5 In
clinical trials across multiple indications at clinically effective doses, duloxetine
has also been shown to increase systolic and diastolic blood pressure by up
to 2mmHg. 25 In a clinical pharmacology study designed to evaluate the
effects of duloxetine on various parameters, at the highest 200mg twice-daily
dose, increases in mean blood pressure were 4.7-6.8mmHg (systolic) and
4.5-7mmHg (diastolic) up to 12 hours after dosing. 25
12.1.4 Program Objectives and General Medicinal Chemistry
Strategy
At the outset of our research program, duloxetine was already in advanced
clinical studies for the treatment of SUI and our realistic object was to identify
a ''best in class'' agent.
Hence our program goal was to identify a chronic use, oral therapy with
once-daily dosing suitable for the treatment of SUI. Our laboratory objectives
were to identify a potent, centrally penetrant, dual SNRI (K i o 10 nM) with a
balance of SRI and NRI activity similar to that of duloxetine, and having
excellent selectivity over DRI and other receptors, ion channels and enzymes
(4100-fold). Preclinical differentiation from duloxetine would be evaluated
and achieved through:
Similar or better ecacy in preclinical models of SUI
Similar or better cardiovascular profile in preclinical models
Weak CYP2D6 inhibition
No significant metabolism by polymorphically expressed cytochrome
P450 (CYP) enzymes
Potential for once-a-day dosing in humans
A new SNRI that satisfied these criteria would not only be a potential ''best
in class'' treatment for SUI but would also have a profile suitable for clinical
evaluation as a treatment for other indications where SNRIs have been shown
to have a beneficial effect.
As part of our research efforts to identify potential new SNRI drug candi-
dates, we adopted a strategy of exploring multiple chemical templates in par-
allel in order to increase our chances of having compounds survive to become
advanced clinical candidates.
A key component of our screen sequence was the evaluation of test com-
pounds in a preclinical in vivo canine model of SUI. 27 Our screening funnel was
designed to identify quality compounds for assessment in this model and sev-
eral in vitro assays were run in parallel to facilitate rapid decision-making for