skip to main content
Language:
Search Limited to: Search Limited to: Resource type Show Results with: Show Results with: Index

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

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

Bioorganic & Medicinal Chemistry Letters, 2011, Vol.21(6), pp.1865-1870 [Peer Reviewed Journal]

Full text available

View all versions
Citations Cited by
  • Title:
    Design of a novel pyrrolidine scaffold utilized in the discovery of potent and selective human β 3 adrenergic receptor agonists
  • Author: 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
  • Description: A novel class of human β -adrenergic receptor agonists was designed in effort to improve selectivity and metabolic stability versus previous disclosed β -AR agonists. As observed, many of the β -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 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 exhibited excellent functional β agonist potency across species with good pharmacokinetic properties in rat, dog, and rhesus monkeys. Early de-risking of this novel pyrrolidine core ( ) via full AMES study supports further research into various new β -AR agonists containing the pyrrolidine moiety. A novel class of human β -adrenergic receptor agonists was designed in effort to improve selectivity and metabolic stability versus previous disclosed β -AR agonists. As observed, many of the β -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 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 exhibited excellent functional β agonist potency across species with good pharmacokinetic properties in rat, dog, and rhesus monkeys. Early de-risking of this novel pyrrolidine core ( ) via full AMES study supports further research into various new β -AR agonists containing the pyrrolidine moiety.
  • Is Part Of: Bioorganic & Medicinal Chemistry Letters, 2011, Vol.21(6), pp.1865-1870
  • Identifier: ISSN: 0960-894X ; E-ISSN: 1464-3405 ; DOI: 10.1016/j.bmcl.2010.12.087
  • Subjects: Β3 Adrenergic Receptor Agonist ; Pyrrolidine Scaffold ; Medicine ; Chemistry ; Anatomy & Physiology
  • Language: English

Searching Remote Databases, Please Wait