Design of a novel pyrrolidine scaffold utilized in the discovery of potent and selective human β3 adrenergic receptor agonists

A novel class of human β3-adrenergic receptor agonists was designed in effort to improve selectivity and metabolic stability versus previous disclosed β3-AR agonists. As observed, many of the β3-AR agonists seem to need the acyclic ethanolamine core for agonist activity. We have synthesized derivatives that constrained this moiety by introduction of a pyrrolidine. This unique modification maintains human β3 functional potency with improved selectivity versus ancillary targets and also eliminates the possibility of the same oxidative metabolites formed from cleavage of the N–C bond of the ethanolamine. Compound 39 exhibited excellent functional β3 agonist potency across species with good pharmacokinetic properties in rat, dog, and rhesus monkeys. Early de-risking of this novel pyrrolidine core (44) via full AMES study supports further research into various new β3-AR agonists containing the pyrrolidine moiety.

Graphical abstractA novel class of human β3-adrenergic receptor agonists was designed in effort to improve selectivity and metabolic stability versus previous disclosed β3-AR agonists. As observed, many of the β3-AR agonists seem to need the acyclic ethanolamine core for agonist activity. We have synthesized derivatives that constrained this moiety by introduction of a pyrrolidine. This unique modification maintains human β3 functional potency with improved selectivity versus ancillary targets and also eliminates the possibility of the same oxidative metabolites formed from cleavage of the N–C bond of the ethanolamine. Compound 39 exhibited excellent functional β3 agonist potency across species with good pharmacokinetic properties in rat, dog, and rhesus monkeys. Early de-risking of this novel pyrrolidine core (44) via full AMES study supports further research into various new β3-AR agonists containing the pyrrolidine moiety.Figure optionsDownload full-size imageDownload as PowerPoint slide