4812
J. E. Dowling et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4809–4813
determine the effect of further substitution on selectivity
and potency.
exhibit better potency than tertiary amides derived from
cyclic amines (15g–i).
The in vitro binding data (Table 2) indicated that simple
alkyl substitution, as with N,N-diethylamide 12c (A2A
Ki = 1 nM), could enhance the A2A affinity but concom-
itantly conferred significant potency toward the A1
receptor (A1 Ki = 40 nM), relative to monosubstituted
compounds 12a,b.
Compound 15e, which incorporates the amino-ethylphe-
nol unit from ZM241385 (3), exhibited high affinity (A2A
Ki = 1 nM) and impressive selectivity (300-fold) against
the A1 receptor.
In summary, we have described the synthesis of a series
of triazolo[1,5-a]pyrazine-derived A2A receptor antago-
nists by a novel route. The compounds obtained
through this route represent potential leads for the
development of analogs with good in vitro potency
and selectivity. Further details of our efforts to optimize
these properties through side-chain modifications will be
made in due course.
We subsequently prepared a series of compounds lack-
ing the benzene ring to determine if the amide substitu-
ents in Table 2 conferred similar in vitro activity when
directly linked to the heterocyclic core. Palladium-med-
iated carbonylation of bromide 10a was employed to
prepare ester 13 (Fig. 8). Hydrolysis of 13 to acid 14, fol-
lowed by amine coupling, afforded the desired amides
(15a–i).
References and notes
The in vitro binding data for this class of compounds of-
fer a clearer picture of the distinct SAR at the A2A and
A1 receptors (Table 3). Secondary amides having an aro-
matic group at the terminus of an alkyl chain (15b–f)
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¨
dppp, MeOH
N
N
CO(g), 14 psi
13
N
10a
(R1 = Me)
DMSO, 80oC
52%
N
R1O2C
O
2M LiOH (aq)
MeOH/THF 70oC
67%
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¨
NH2
N
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HATU, iPr2NEt
N
R2
N
amine, DMF
N
14
(R1 = H)
O
O
15a-i
Figure 8. Synthesis of amides 15a–i by Pd-catalyzed carbonylation.
Table 3. Affinities of 15a–i toward rat A2A and A1 receptors, as
measured in radioligand binding assaysa
Compound
R2
A2A (rat)
Ki (nM)
A1 (rat)
Ki (nM)
15a
15b
HNBu
1
2
120
14
HN
Ph
N
Ph
15d
15e
15f
15g
15h
15I
27
1
160
320
Me
OH
HN
HN
28
240
Ph
>250
>250
>250
>250
>250
>250
N
N
N
O
NBn
N
N
a Refer to Tables 1 and 2 for details regarding rat membrane based
radioligand binding assays.