Discovery of benzamides as potent human β3 adrenergic receptor agonists

Bioorg Med Chem Lett. 2016 Jan 1;26(1):55-9. doi: 10.1016/j.bmcl.2015.11.030. Epub 2015 Nov 11.

Abstract

The paper will describe the synthesis and SAR studies that led to the discovery of benzamide (reverse amide) as potent and selective human β3-adrenergic receptor agonist. Based on conformationally restricted pyrrolidine scaffold we discovered earlier, pyrrolidine benzoic acid intermediate 22 was synthesized. From library synthesis and further optimization efforts, several structurally diverse reverse amides such as 24c and 24i were found to have excellent human β3-adrenergic potency and good selectivity over the β1 and β2 receptors. In addition to human β1, β2, β3 and hERG data, PK of selected compounds will be described.

Keywords: Bioisostere; Overactive bladder; Pyrrolidine scaffold; Reverse amide; β(3) adrenergic receptor agonist.

MeSH terms

  • Adrenergic beta-3 Receptor Agonists / chemical synthesis
  • Adrenergic beta-3 Receptor Agonists / chemistry
  • Adrenergic beta-3 Receptor Agonists / pharmacology*
  • Benzamides / chemical synthesis
  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Molecular Structure
  • Receptors, Adrenergic, beta-3 / metabolism*
  • Structure-Activity Relationship

Substances

  • Adrenergic beta-3 Receptor Agonists
  • Benzamides
  • Receptors, Adrenergic, beta-3