Chemistry Reference
In-Depth Information
of PNU-282987 (1 or 3mg kg
1
iv) significantly reversed the d-amphetamine-
induced gating deficit; in contrast, administration of vehicle to control rats did
not normalize the deficit. Furthermore, PNU-282987 (1mg kg
1
iv) had no
significant effect on normal gating in anesthetized rats.
23
With this evidence
as a starting point, a valid template for chemistry, and a deep screening strategy
to serve in the identification of an in vivo active compound, we were poised to
identify clinically viable compounds.
As described earlier, HTS and parallel synthetic chemistry identified quinu-
clidine amide PNU-282987 as a potent and selective agonist of the a7
nAChR.
17
PNU-282987 had been alleged to be a useful treatment for various
CNS diseases; however,
24
preclinical cardiac safety studies revealed significant
hERG potassium channel activity. Thus the program objective was to identify a
novel quinuclidine aryl amide with in vitro and in vivo profiles equal to or better
than that of PNU-282987.
15.3 Pursuing the First Clinical Candidate by Defining
the Desired Properties to Deliver a High-Quality
Molecule
Another potent a7 nAChR agonist identified during parallel synthesis was
indole 2 (Figure 15.3). Although azabicyclic systems had been identified in the
literature for the treatment of various CNS disorders,
25
the team believed that
indole 2 provided an avenue to novel analogs with improved safety profiles. To
this end, a large number of custom acid fragments were prepared via multistep
syntheses to build the SAR systematically around 6,5-fused heterocyclic amides
of the 3-aminoquinuclidine.
20,26,27
The first set of analogs focused on aryl rings
with two heteroatoms in the five-membered ring (Figure 15.4). Benzoxazole 3
showed anity and functional activity at the a7 receptor equal to that of PNU-
282987 (a7 nAChR, K
i
¼
32 nM; a7/5-HT
3
,EC
50
¼
130 nM). Unfortunately,
the compound showed no stability in rat liver microsomes (RLM) (4%
remaining after 1 h). Regioisomeric benzoxazole 4 was significantly less potent
than PNU-282987. Interestingly, benzothiazole 5, a sulfur isostere of benzox-
azole 3, showed poor activity toward the a7 nAChR, but regioisomeric ben-
zothiazole 6 demonstrated strong anity and functional activity equal to that
of PNU-282987. Whereas indazole 7 showed low anity for the a7 nAChR,
indazole 8 exhibited activity similar to that of PNU-282987. Benzimidazole 9
N
N
O
O
N
H
H
Cl
PNU-282987
2
Figure 15.3
6,5-Fused bicyclic heteroaryl amides of the 3-aminoquinuclidine prototype.
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