306
E. Elzein et al. / Bioorg. Med. Chem. Lett. 16 (2006) 302–306
relative to 3. Even though, the 4-Cl phenyl analog 18
showed 2-fold decreased A2B-AdoR binding affinity
(Ki = 39 nM) than its oxadiazole regio isomer 5, it dis-
played more selectivity for the A2B-AdoR versus other
three receptor subtypes (A1/A2B, A2A/A2B, and A3/A2B
selectivity ratios of 74, >128, and >218, respectively).
The 4-CF3 analog, compound 20, showed at least 2-fold
increase in A2B-AdoR binding affinity (Ki = 21 nM) rel-
ative to its regio isomer 6. In addition, compound 20
antagonists that may have potential use as therapeutic
agents for treatment of asthma.
References and notes
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M. Pharmacol. Rev. 1994, 46, 143.
showed much improved selectivity profile for the A2B
-
3. Kirschenbaum, A. S.; Hettinger, B.; Day, Y. J.; Gilfilian,
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13. (a) In previous communications, we have shown that A2B
adenosine receptor antagonists containing an amide bond
have less liver S9 metabolic stability. MRS-1754 (1), which
contains an amide bond, is also metabolically unstable. In
addition, we have successfully replaced the amide bond
with oxazoles, isoxazoles, and oxadiazoles, and that
resulted in compounds with enhanced metabolic stability;
(b) Zablocki, J.; Kalla, R.; Perry, T.; Palle, V.; Varkhed-
kar, V.; Xiao, D.; Piscopio, A.; Maa, T.; Gimbel, A.; Hao,
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AdoR relative to 6 (A1/A2B, A2A/A2B, and A3/A2B selec-
tivity ratios of >285, >238, and 61, respectively). Unlike
in the 3-phenyl-1,2,4-oxadiazole class of compounds
(Table 1, where unsubstituted phenyl ring was optimal
for both, binding affinity and selectivity for the A2B
-
AdoR) and in this series of 5-phenyl-1,2,4-oxadiazoles
(Table 2), a strong electron-withdrawing group in the
4-position of the phenyl ring provided the most active
and selective analog (compound 20). One could envision
the 5-phenylisoxazole series (Table 3) as a direct analog
of the 3-phenyl-1,2,4-oxadiazole series where the 4-ni-
trogen atom in the 3-phenyl-1,2,4-oxadiazole ring is
isosterically replaced with a carbon atom. The isoxazole
analog 30 showed 2-fold decreased A2B-AdoR binding
affinity (Ki = 48 nM) relative to the oxadiazole analog
20. In addition, compound 30 displayed much lower
selectivity for the A2B-AdoR versus A1, A2A, and A3-
AdoRs relative to 20. A similar trend was observed
when comparing the isoxazole analog 29 to the oxadiaz-
ole analog 18. In general, the 5-phenylisoxazole series
was less active and selective for the A2B-AdoR in com-
parison to the other two oxadiazole classes of com-
pounds. It is noteworthy that some of these new
analogs showed good oral bioavailability in rats. Com-
pound 5, for instance, displayed 22% oral bioavailability
in rats when dosed at 1 mg/Kg (in DMSO/ethanol/
PEG300/50 mM n-methylglucamine) (2.5:10:20:67.5)
with AUC of 2330 ng h/mL and t1/2 of 1.5 h.
In summary, we have discovered a novel class of A2B
-
AdoR antagonists. Bioisosteric replacement of the
amide bond in compound 2 with different heterocyclic
5-membered rings (1,2,4-oxadiazoles and isoxazoles)
resulted in compounds with high affinity and selectivity
for the A2B-AdoR. Compound 4 is among the most ac-
tive and selective A2B-AdoR antagonist known to date.
Considering the fact that only a few high affinity and
selective A2B-AdoR antagonists are available, this new
series of compounds constitutes a significant addition
to the field and might be useful as pharmacological
tools. In addition, these new analogs may serve as leads
to discover additional potent and selective A2B-AdoR
14. Patani, G. A.; LaVoie, E. J. Chem. Rev. 1996, 96, 3147,
and references therein.
15. Daly, J. W.; Padgett, W.; Shamim, M. T.; Butts-Lamb, P.;
Waters, J. J. Med. Chem. 1985, 28, 487.