It was hypothesised that the increased activity of indoles bearing smaller groups at the C2 position described above would be derived from the con-formational preference of conformer A over conformer B as a result of steric

Amide conformer A Amide conformer B

Fig. 6.3 Structures of amide conformers A and B.

effects (Figure 6.3) [221]. Based on this hypothesis, indazoles and indo-lopyridones, such as (356) and (357) were designed. For (356), it was predicted that conformer A would be preferred over conformer B, as the result of an intramolecular stereoelectronic interaction. Actually, (356) was more potent than all of the indole derivatives mentioned above. The conforma-tionally constrained indolopyridone (357) had the most potent activity in the series [Ki(CB2) = 1.0 nM]. In the in vivo model, (357) exhibited inhibition activity against LPS-induced TNF-a release both after i.v. and oral administration. CB2-selective indazole derivatives, such as (358), were also reported from the research group of the University of Connecticut [222]. The K values of (358) for CB2 and CB1 were 0.15 and 6.84 nM, respectively. Another type of C3 amido-indole, exemplified by (359), was disclosed by Sanofi Synthelabo [223].

(356) Ki(CB2) = 2 nM
(357) Ki(CB2) = 1 nM
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