Chemistry Reference
In-Depth Information
MW 288
HLM, T
1/2
>120 min
H
O
clog P 2.4
h.heps, T
1/2
144 min
Log D
7.4
0.5
CYP2D6 inh., IC
50
5.7
M
µ
N
pKa 10
CYP1A2, 2C9, 3A4 inh., IC
50
>30
µ
M
TPSA 25
MDCK-mdr1, AB/BA 17/26
Me
11
K
+
, hERG, IC
50
14.4
µ
Μ
Me
Na
+
, site 2, IC
50
8.9
SRI, IC
50
9 nM
µ
M
Ca
2+
, L -type diltiazem site, IC
50
12
µ
M
NRI, IC
50
7 nM
DRI, IC
50
727 nM
Figure 12.8
Profile of compound 10. hERG
¼
human Ether-a-go-go Related Gene;
h.heps
¼
human hepatocytes; HLM
¼
human liver microsomes; MDCK
mdr-1
¼
Madin-Darby Canine Kidney cell line overexpressing the mdr-1
gene which encodes P-glycoprotein.
compound 12 for which dealkylation was found to be the primary route of
metabolism (480%). Unfortunately, the primary metabolizing enzyme for 12
was found to be CYP2D6, whereas for compound 11 it was CYP3A4, illus-
trating the impact small structural modifications can have on metabolic path-
ways. We then elected to block the N-dealkylation of 12 by replacing the
4-tetrahydropyranyl substituent by an amide group (Figure 12.9).
SAR investigations in this novel carboxamide template have been reported
and were greatly facilitated by the simplicity of the chemistry route.
35
From
these analyses, compound 13 emerged as combining potent dual SNRI activity
with selectivity against the dopamine transporter. Compound 13 also exhibited
good membrane permeability in the CaCO-2 cell line and good metabolic
stability both in human liver microsomes and human hepatocytes, predictive of
a low in vivo clearance. Compound 13 had no significant inhibition of all major
CYP450 enzymes, modest anity for the hERG channel (Figure 12.10) and no
significant off-target pharmacology when assessed against a panel of 150
receptors, enzymes and ion channels (200-fold selectivity for SNRI activity,
CEREP/Bioprint
t
). When the metabolic profile of compound 13 was investi-
gated in an in vitro human microsomal preparation, the compound was found
to be so metabolically stable that no measurable turnover could be detected. As
a result, assessment of the CYP2D6 contribution to metabolism was not pos-
sible. Should 13 have progressed further, the potential for increased exposures
in poor metabolisers would therefore have had to be monitored in clinical
studies. Finally, pharmacokinetic data in the dog showed that compound 13
had low clearance, a low volume of distribution, a long half-life and high
bioavailability, all predictive of a human pharmacokinetics profile consistent
with our project objectives.
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