Combination of a Beta adrenoceptor modulator and a norepinephrine-serotonin uptake inhibitor for the treatment of obesity.

We report the novel combination of a selective beta adrenoceptor modulator and a norepinephrine-serotonin uptake inhibitor (sibutramine) with potential for the treatment of obesity. The synthesis and characterization of 6-[4-[2-[[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino]-2-methylpropyl]phenoxy]pyridine-3-carboxamide (LY377604), a human β3-adrenergic receptor agonist and β1- and β2-adrenergic receptor antagonist with no sympathomimetic activity at the β1- and β2-adrenergic receptors, is reported. Some in vivo data in both rats and humans is presented.

Potent oxindole based human beta3 adrenergic receptor agonists.

The synthesis and biological evaluation of a series of oxindole beta(3) adrenergic receptor agonists is described. A modulation of rat atrial tachycardia was observed with substitution at the 3-position of the oxindole moiety.

Potent benzimidazolone based human beta(3)-adrenergic receptor agonists.

The synthesis and biological evaluation of a series of benzimidazolone beta(3) adrenergic receptor agonists are described. A trend toward the reduction of rat atrial tachycardia upon increasing steric bulk at the 3-position of the benzimidazolone moiety was observed.

Orally bioavailable GSK-3alpha/beta dual inhibitor increases markers of cellular differentiation in vitro and bone mass in vivo.

Unlabelled: GSK-3, a component of the canonical Wnt signaling pathway, is implicated in regulation of bone mass. The effect of a small molecule GSK-3 inhibitor was evaluated in pre-osteoblasts and in osteopenic rats. GSK-3 inhibitor induced osteoblast differentiation in vitro and increased markers of bone formation in vitro and in vivo with concomitant increased bone mass and strength in rats.