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In-Depth Information
ideal because it was metabolized slowly and had linear PK in the clinic.
In addition, it demonstrated a modest improvement in the CogState test
battery in healthy volunteers at the lowest dose tested (5 mg); and (3) it
had fewer and less severe cardiovascular side effects than its counterpart,
PHA-568487.
55
Key design principles in this effort included favorable physicochemical
properties, in vitro ADME assays, and a pharmacophore model for hERG to
minimize this potential liability. Specifically, compounds with molecular weight
o
400 and clog P
o
3.0 were targeted since we were mindful of the basic amine
within the molecule. We believed that these design criteria would assist in the
rapid optimization of the PK profile as well as reduce known risks associated
with lipophilic, basic compounds.
56
With respect to in vitro ADME assays, we
targeted compounds with HLM clearance
o
10mLmin
1
kg
1
, high perme-
ability [as shown in a Madin Darby canine kidney cell line (MDCK)] A
B
410
10
6
cm s
1
, and low potential for PgP eux (MDR BA/AB ratio
o
2.0).
This lead series was derived from screening the Pfizer chemical file and from
the primary and patent literature. Starting from known quinuclidine pheny-
lurethane 23, the first design cycle consisted of reversing the orientation of the
carbamate and including the nitrogen atom of the carbamate within the bicyclic
ring to give compound 24 (Figure 15.12). This design was greatly facilitated by
our previous use of 1,4-diazabicylo[3.2.2]nonane in a quinoline antibiotic
program, giving us ample supply to establish the SAR.
57,58
This SAR revealed
that one of the major liabilities with the phenyl carbamate series was main-
taining the balance of good potency (K
i
o
20 nM) and good functional activity
(i.e., full agonist activity when compared to nicotine).
59
In an attempt to
address this challenge, the team envisioned utilizing heterocyclic replacements
of the carbamate functional group of 24 and developed the SAR of benzoxazole
and azabenzoxazoles 25 as heterocyclic replacements of the phenyl carbamate.
The preparation of benzoxazole and azabenzoxazole analogs was straight-
forward.
60
The a7 nAChR and 5-HT
3
binding activities and a7 nAChR
functional data for a number of key monosubstituted benzoxazole and
unsubstituted azabenzoxazole analogs are shown in Figure 15.13. Unsub-
stituted benzoxazole analog 27 was characterized as a full agonist (vs. 50 mM
nicotine) in a Xenopus oocyte assay, with robust a7 nAChR anity and
equivalent potency at the 5-HT
3
receptor. Replacing the carbamate functional
-
6
Y
R
Br
Br
O
5
O
O
X
N
N
O
N
O
H
N
N
N
25
:X=CHorN,Y=CHorN
23
,
α
7
K
i
=167nM,90%ag
WO 97 / 30998 Astra
24
,
α
7
K
i
=36nM,158%ag
(SR-180711)
Figure 15.12
Rational design of the benzoxazole and azabenzoxazole series.
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