Human beta3 adrenergic receptor agonists containing cyclic ureidobenzenesulfonamides

Area of Science:

• Pharmacology
• Medicinal Chemistry

Background:

• The beta3 adrenergic receptor (β3 AR) plays a role in metabolic processes.
• Developing selective β3 AR agonists is a therapeutic goal for conditions related to energy expenditure.

Purpose of the Study:

• To synthesize and evaluate novel 5-membered ring urea derivatives as human beta3 adrenergic receptor agonists.
• To assess the potency, selectivity, and in vivo efficacy of these novel compounds.

Main Methods:

• Synthesis of 5-membered ring urea analogs.
• In vitro receptor binding and functional assays to determine potency (EC50) and selectivity against β1 and β2 adrenergic receptors.
• In vivo studies in rhesus monkeys to assess lipolytic activity (ED50) and cardiovascular effects.
• Oral absorption studies in dogs.

Main Results:

• Compounds L-760,087 (4a) and L-764,646 (5a) exhibited potent partial agonism at the human β3 AR (EC50 = 18 nM and 14 nM, respectively).
• These agonists demonstrated excellent selectivity over β1 and β2 adrenergic receptors.
• In vivo, they effectively stimulated lipolysis in rhesus monkeys (ED50 = 0.2 mg/kg and 0.1 mg/kg, respectively) with minimal impact on heart rate.
• Oral absorption in dogs was superior compared to other urea analogs.

Conclusions:

• Novel 5-membered ring urea derivatives are potent and selective human beta3 adrenergic receptor agonists.
• These compounds show promising efficacy in stimulating lipolysis in vivo with a favorable safety profile regarding heart rate.
• Improved oral absorption suggests potential for therapeutic development.