Anthony J. Shuker

The Application of High-Throughput Synthesis And Purification To The Preparation Of Ethanolamines

Abstract A 48 compound library of structurally diverse ethanolamines was prepared using a parallel synthesis approach. The synthetic paradigm employed a solution phase epoxide-opening reaction followed by rapid purification by ion exchange chromatography to yield products with near-analytical purity. An array of epoxides and primary amines, arranged in an 8×6 matrix, were reacted in the presence of an in situ silylating agent to form 48 individual compounds with an average yield of 75% and an average purity of 92.3%.

Aryl propanolamines : comparison of activity at human β3 receptors, rat β3 receptors and rat atrial receptors mediating tachycardia

The in vitro activity of four aryl propanolamines was compared to two prototypic β3 receptor agonists, CGP 12177 and CL316243 at the human β3 receptor, the rat β3 receptor in the stomach fundus and receptors mediating atrial tachycardia. L‐739,574 was the most potent (EC50=9 nM) and selective agonist at the human β3 receptor with high maximal response (74% of the maximal response to isoproterenol). A phenol‐biaryl ether analogue possessed modest affinity for the human β3 receptor (EC50=246 nM), but was highly efficacious with a maximal response 82% of the maximal response to isoproterenol. The other derivatives were intermediate in potency with low maximal responses. These agonists at the human β3 receptor did not activate the rat β3 receptor in the rat stomach fundus. In fact, the aryl propanolamines (10−6 M) inhibited CL316243‐induced activation of the rat β3 receptor. Thus, agonist activity at the human β3 receptor translated into antagonist activity at the rat β3 receptor. L739,574 and the phenol biaryl ether increased heart rate via β1 receptors. Although CGP12177 produced atrial tachycardia, neither the indole sulphonamide nor biphenyl biaryl ether did, although both had high affinity for the human β3 receptor. Thus, the atrial tachycardic receptor was not identical to the human β3 receptor. These studies (a) characterized four aryl propanolamines with high affinity at the human β3 receptor, (b) found that they were antagonists at the rat β3 receptor, an observation with profound implications for in vivo rat data, and (c) established that the rodent atrial non‐β1, β2 or β3 tachycardic receptor was also unrelated to the human β3 receptor.

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.