Design of a novel pyrrolidine scaffold utilized in the discovery of potent and selective human beta sub(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, Di Salvo, Jerry, 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: 15.03.2011
• Subjects: Macaca mulatta
• ISSN: 0960-894X
• DOI: 10.1016/j.bmcl.2010.12.087

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