A series of azine analogs (1) of the CB1 inverse agonist, taranabant�, with lower LogD cf. to the lead, exhibited similar or improved food intake and weight loss effects, in rats, despite lower brain: plasma ratios. It was speculated that the decreased LogD of these compounds was the cause of their decreased propensity to cross the blood / brain barrier. We were interested in determining whether these polar analogs can achieve comparable food intake / weight loss effects with the lower brain : plasma ratios. This question constitutes a fundamental issue for CB1R as a target as it has been proposed that adequate in vivo efficacy is likely due to primarily engaging the CNS-expressed receptors. The synthesis, pharmacokinetic and pharmacodynamic properties of these potent azine CB1 inverse agonist of the clinical candidate taranabant�, will be discussed.

Orally active polar analogs of taranabant, as CB1 inverse agonist

244th National Meeting (2012)

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