Biarylaniline phenethanolamines as potent and selective beta3 adrenergic receptor agonists

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Drug Discovery

Background:

• Beta(3) adrenergic receptors (ARs) are implicated in metabolic regulation.
• Developing selective beta(3) AR agonists is a therapeutic strategy for type 2 diabetes.
• Phenethanolamine aniline derivatives represent a potential class of beta(3) AR modulators.

Purpose of the Study:

• To synthesize and characterize novel phenethanolamine aniline agonists.
• To evaluate the potency and selectivity of these compounds for beta(3) ARs.
• To assess the pharmacokinetic properties and in vivo efficacy of promising candidates.

Main Methods:

• Chemical synthesis of phenethanolamine aniline analogues.
• In vitro receptor binding and functional assays using Chinese hamster ovary (CHO) cells expressing beta ARs.
• In vivo pharmacokinetic studies in dogs and dose-dependent response studies in mice.

Main Results:

• Several analogues exhibited high potency and selectivity for beta(3) ARs over beta(1) and beta(2) ARs.
• Selected compounds demonstrated good oral bioavailability (>25%) and half-lives (≥1.5 h) in dogs.
• Compounds 36, 38, and 44 showed potent beta(3) AR mediated responses in mice.

Conclusions:

• Compound 38 possesses favorable in vitro and in vivo characteristics, including ease of synthesis and superior pharmacokinetics.
• Compound 38 is identified as a development candidate for type 2 diabetes treatment.
• The synthesized phenethanolamine aniline derivatives show promise as beta(3) AR agonists.