1 research outputs found
6āAlkoxy-5-aryl-3-pyridinecarboxamides, a New Series of Bioavailable Cannabinoid Receptor Type 1 (CB1) Antagonists Including Peripherally Selective Compounds
We identified 6-alkoxy-5-aryl-3-pyridinecarboxamides
as potent
CB1 receptor antagonists with high selectivity over CB2 receptors.
The series was optimized to reduce lipophilicity compared to rimonabant
to achieve peripherally active molecules with minimal central effects.
Several compounds that showed high plasma exposures in rats were evaluated
in vivo to probe the contribution of central vs peripheral CB1 agonism
to metabolic improvement. Both rimonabant and <b>14g</b>, a
potent brain penetrant CB1 receptor antagonist, significantly reduced
the rate of body weight gain. However, <b>14h</b>, a molecule
with markedly reduced brain exposure, had no significant effect on
body weight. PK studies confirmed similarly high exposure of both <b>14h</b> and <b>14g</b> in the periphery but 10-fold lower
exposure in the brain for <b>14h</b>. On the basis of these
data, which are consistent with reported effects in tissue-specific
CB1 receptor KO mice, we conclude that the metabolic benefits of CB1
receptor antagonists are primarily centrally mediated as originally
believed