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O
O
R
N
O
N
N
N
N
26
α
7
K
i
= 739 nM, 99% ag
5-HT
3
K
i
= 3993 nM, antag
27
R=H;
α
7
K
i
= 22.5 nM, 183% ag
5-HT
3
K
i
=13nM,antag
28
R=Cl;
K
i
=1.92nM,122%ag
5-HT
3
K
i
= 1.2 nM, antag.
α
7
N
N
O
O
O
O
N
N
N
N
N
N
N
N
N
N
N
N
N
N
29
α
7
K
i
= 30.3 nM, 220% ag
5-HT
3
K
i
= 579 nM, antag
30
α
7
K
i
= 312 nM, 156% ag
5-HT
3
K
i
=2120nM,antag
31
α
7
K
i
= 309 nM, 186% ag
5-HT
3
K
i
= 162 nM, antag
32
α
7
K
i
= 40.6 nM, 182% ag
5-HT
3
K
i
=92nM,antag
Figure 15.13
Azabenzoxazole structure-activity relationships leading to the dis-
covery of the 4-azabenzoxazole chemotype.
group with a heterocyclic benzoxazole proved a viable option, as 27 was
32
times more potent than 26 at the a7 nAChR, confirming our design hypothesis.
Substitution with a halogen or small alkyl group at the 5- or 6-position of the
benzoxazole ring generally increased potency (exemplified by 28) for the a7
nAChR, but these substitutions did not improve 5-HT
3
selectivity. Four
monoaza-benzoxazole regioisomers (29-32) were also prepared in an attempt
to broadly define the SAR for this core. Both 4-azabenzoxazole 29 and 7-
azabenzoxazole 32 demonstrated potent a7 nAChR anities, maintained full
agonist activity in the functional assay, and demonstrated potential for
improved selectivity over the 5-HT
3
receptor (20
and 2
, respectively),
pointing to a promising direction for additional SAR studies.
Through extensive SAR development, we determined that analogs of the 4-
azabenzoxazole template 29 generally displayed greater binding anity at the
a7 nAChR than their counterparts in the 7-azabenzoxazole template 32. The
SAR of the 4-azabenzoxazole series is summarized in Figure 15.14.
60
Sub-
stitution at the 7-position resulted in compounds with reduced anity for the
a7 nAChR, whereas 5- and 6-position substitutions resulted in compounds with
robust potency (a7 nAChR, K
i
o
20 nM) and full agonist activity relative to
nicotine. Halogens, nitrile, and small alkyl groups (e.g. Me), phenyl groups,
and aryl ethers were preferred at the 6-position, and phenyl, pyrrolidinyl, small
alkyl groups (e.g. Me, Et), and aryl ethers were preferred at the 5-position.
Additionally, bis-substitution at the 5- and 6-position was tolerated and in
some cases synergistic when examining off-target pharmacology such as hERG
anity and in vitro micronucleus findings (vide infra).
A group of high-interest compounds (33-36) were further profiled in key
selectivity assays (Table 15.2).
61
All of these compounds were potent at the a7
nAChR in binding assays and demonstrated functional agonism both in whole-
cell patch-clamp assays, in which a7 nAChR was expressed in oocytes, as well
as in an a7/5-HT
3
chimera FLIPR assay. These compounds also displayed
selectivity over other nicotinic receptor subtypes (490
vs. a4b2anda3b4
nAChRs). This subset of compounds displayed modest to good selectivity
B
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