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

• Published in: Bioorganic & medicinal chemistry letters 2011-03, Vol.21 (6), p.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: Article
• Language: English
• Subjects: Adrenergic beta-Agonists - chemistry; Adrenergic beta-Agonists - pharmacology; agonists; Biological and medical sciences; Catecholaminergic system; chemistry; Crystallography, X-Ray; dogs; Drug Discovery; ethanolamine; Humans; Macaca mulatta; Medical sciences; metabolites; Models, Molecular; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; pharmacokinetics; Pharmacology. Drug treatments; Pyrrolidines - chemistry; rats; Receptors, Adrenergic, beta-3 - drug effects
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.12.087

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.