Chemistry Reference
In-Depth Information
Table 15.3 Selected physicochemical properties, ADME, and pharmacoki-
netic data for 34.
a
hCL (mL/min/kg)
o
5.3
MW
cLogP
logD
TPSA
pKa
HBD
258
1.57
0.36
45.4
8.86
0
O
MDR BA/AB
0.8
N
MDCK (10-6 cm/s)
18.0
N
N
Oral bioavailability, F(%) (rat)
73
N
Plasma protein binding (fu) (rat/
mouse/human)
0.78/
0.91/
0.85
Brain (ng/g) 3640
Plasma (ng/ml) 1160
Brain/Plasma 3.2
CSF (nM) 3230
a
ADME, absorption, distribution, metabolism, and excretion; CSF, cerebrospinal fluid; HBD,
hydrogen bond donor; MDCK, Madin Darby canine kidney; MDR, multidrug resistance; MW,
molecular weight; TPSA, topological polar surface area.
34
(CP-810123)
The physicochemical properties, in vitro characteristics, ADME, and PK
data for 34 are captured in Table 15.3.
60
These properties clearly aligned with
our design goals of low molecular weight, low clog P and clog D, and topo-
logical polar surface area consistent with effective CNS drugs.
62
Compound 34
showed excellent solubility and ADME attributes and was metabolically stable
in the presence of HLM (hCl
h
o
5.3mLmin
1
kg
1
), which predicts a long half-
life. The compound was also well absorbed (MDCK A
BZ18
10
6
cm s
1
),
-
1).
63
Sub-
sequent in vivo studies validated these in vitro results: 34 demonstrated high oral
bioavailability and favorable brain/plasma ratios in rats, with no evidence of
impaired brain penetration using PgP knockout mice. Furthermore, the ratio of
[cerebrospinal fluid (CSF)]/[total plasma] versus fraction unbound in PgP stu-
dies was 0.8, suggesting no disequilibrium and ready distribution to the brain.
The overall profile of 34 prompted further in vivo characterizations. Ex vivo
binding studies evaluated the exposure of 34 at the target site after systemic
administration. Receptor binding under these conditions is dependent on the
access of the compound to the receptor and is therefore influenced by brain
uptake, protein binding, and other partitioning that may occur in the brain.
Receptor occupancy was determined in the hippocampal brain regions of rats
30 min after sc injections of 34 or vehicle (3 animals/dose group) using [
125
I]-a-
bungarotoxin. The dose- and ex vivo-derived receptor occupancy relationship
yielded an ED
50
of 0.34mg kg
1
for 34, clearly establishing that 34 occupied its
target of action.
Compound 34 was evaluated in two rodent models of cognition, d-amphe-
tamine-induced gating and NOR. In the auditory gating experiment, 34 sig-
nificantly improved auditory gating at 0.3 and 1.0mg kg
1
sc (p
o
0.05). These
data were used to establish a minimum effective dose of 34 at0.3mgkg
1
, and
the free plasma exposure achieved in rats associated with this dose was
326 nM approximately 40 min after dosing. Additionally in rats, quantitative
with no evidence of PgP eux (MDR1/MDCK B
-
A/A
-
B
E
Search WWH ::
Custom Search