Chemistry Reference
In-Depth Information
Table 7.2 Permeability and brain penetration data for key polar analogues of 3.
Rat CNS
studies
brain:blood
Rat CNS
studies CSF:free
blood
Caco-2
(A-B/B-A)
Compound R
2
pK
a
3
H
9.3
21/8
14:1
1:1
10
CONH
2
8.5
-
-
1:1
11
CONHMe
8.8
26/11
-
1:1
14
SO
2
NH
2
8.4
18/7
16:1
2.6:1
15
SO
2
NHMe
-
-
-
0.3:1
HLM, T
1/2
> 120 min
RLM, T
1/2
= 23 min
HLM, T
1/2
> 120 min
RLM, T
1/2
>120 min
NHMe
NHMe
O
O
S
Rat PK
V
D
= 52 L/kg
Cl
blood
= 71 mL/min/kg
T
1/2
= 5 h
T
max
= 4 h
Rat PK
V
D
= 19 L/kg
Cl
blood
= 60 mL/min/kg
T
1/2
= 4 h
T
max
= 1 h
Human PK prediction
V
D
= 7-12 L/kg
Cl
blood
= 6-17 mL/min/kg
T
1/2
~ 8-13 h
T
max
< 2 h
H
2
N
Cl
Cl
3
14
Cl
Cl
Figure 7.3
Compound 14 was progressed to rat PK studies and, as hoped, it showed a
significantly reduced volume of distribution relative to 3 (19 L kg
1
vs.
52 L kg
1
, unbound volume 660 L kg
1
vs. 1900 L kg
1
) (Figure 7.3). Very
importantly, this also translates to a significantly reduced T
max
relative to 3 (1 h
vs. 4 h). Despite being stable in rat liver microsomes (RLM) (t
1/2
4 120min), 14
shows moderate clearance in vivo, resulting in a half-life of 4 h. A dog PK study
was also carried out on sulfonamide 14 and gave results consistent with those
seen in the rat (V
D
¼
12 L kg
1
, Cl
blood
¼
11mLmin
1
kg
1
, t
1/2
¼
7 h). Scaling
to man gave a prediction of a volume of 7-12 L kg
1
and a T
max
of less than 2 h.
Because turnover is not seen in rat, dog or human microsomes, clearance in rat
and dog appears to be the result of an active clearance process rather than
metabolic turnover. As a result, clearance in man was predicted based on
scaling from rat and dog, leading to a half-life prediction of 8-13 h.
7.3.2 Clinical Data for UK-373911
Although predictions for volume were at the upper end of what we had targeted
and the higher end of the predicted clearance range presented a risk of low
bioavailability in man, compound 14 (UK-373911) was considered to be
suitable for progression and was selected for clinical development. Compound
14 showed no significant off-target pharmacology, successfully completed
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