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

✍ Scribed by Gregori J. Morriello; Harvey R. Wendt; Alka Bansal; Jerry Di Salvo; Scott Feighner; Jiafang He; Amanda L. Hurley; Donna L. Hreniuk; Gino M. Salituro; Marat Vijay Reddy; Sheila M. Galloway; Katherine K. McGettigan; George Laws; Crystal McKnight; George A. Doss; Nancy N. Tsou; Regina M. Black; Judy Morris; Richard G. Ball; Anthony T. Sanfiz; Eric Streckfuss; Mary Struthers; Scott D. Edmondson

• Publisher: Elsevier Science
• Year: 2011
• Tongue: English
• Weight: 822 KB
• Volume: 21
• Category: Article
• ISSN: 0960-894X
• DOI: 10.1016/j.bmcl.2010.12.087

✦ Synopsis

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