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 272

Duloxetine Peak Urethral Pressure

*

45

*

40

*

35

30

25

20

15

10

5

0

0 nM 2.6 nM 4.5 nM 15 nM 60 nM

Figure 12.3

Increases in PUP versus free plasma drug concentration for duloxetine in
an anaesthetized dog model of SUI. Significance relative to control noted
thus *; P o 0.05.

Me

NH

N

R 3

R 2

N

R 3

O

Ring A

Ring A

Ring B

Ring B 6

5

R 4

R 1

Figure 12.4

Structures of lead series.

12.2 Medicinal Chemistry: Hit, Lead and Candidate
Generation
As discussed in the introduction, we chose to prosecute this medicinal chem-
istry program with multiple lead-series in parallel. However, for clarity these
will be discussed in sequence in this section. One of our two main leads con-
sisted of a proprietary series of diphenyl ethers 5 (Figure 12.4), which had
initially been prosecuted in the discovery of novel selective serotonin reuptake
inhibitor (SSRI) development candidates. 28
Our second main lead resulted from in silico virtual screening of the Pfizer
compound file, which identified biarylpiperazines 6 as a structure which pos-
sessed interesting levels of SNRI pharmacology and attractive lead-like prop-
erties (Figure 12.4).
Structure-activity relationships (SAR) within the B -ring of diphenyl ether 5
quickly identified a 2,4-disubstitution pattern that was important for dual
SNRI potency. Further optimisation to a 2-OMe þ 4-Cl substitution alongside