Design of a novel pyrrolidine scaffold utilized in the discovery of potent and selective human β 3 adrenergic receptor agonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 6; pp. 1865 - 1870
• Main Authors: Morriello, Gregori J., Wendt, Harvey R., Bansal, Alka, Salvo, Jerry Di, Feighner, Scott, He, Jiafang, Hurley, Amanda L., Hreniuk, Donna L., Salituro, Gino M., Reddy, Marat Vijay, Galloway, Sheila M., McGettigan, Katherine K., Laws, George, McKnight, Crystal, Doss, George A., Tsou, Nancy N., Black, Regina M., Morris, Judy, Ball, Richard G., Sanfiz, Anthony T., Streckfuss, Eric, Struthers, Mary, Edmondson, Scott D.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 2011
• Subjects: Pyrrolidine scaffold; β3 Adrenergic receptor agonist; β3 Adrenergic receptor agonist; Pyrrolidine scaffold
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.12.087

A novel class of human β 3-adrenergic receptor agonists was designed in effort to improve selectivity and metabolic stability versus previous disclosed β 3-AR agonists. As observed, many of the β 3-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 β 3 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 β 3 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 β 3-AR agonists containing the pyrrolidine moiety. A novel class of human β 3-adrenergic receptor agonists was designed in effort to improve selectivity and metabolic stability versus previous disclosed β 3-AR agonists. As observed, many of the β 3-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 β 3 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 β 3 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 β 3-AR agonists containing the pyrrolidine moiety.