Selective beta 3-adrenergic agonists of brown adipose tissue and thermogenesis. 1. [4-[2-[(2-Hydroxy-3-phenoxypropyl)amino]ethoxy]phenoxy]acetates

J Med Chem. 1992 May 15;35(10):1751-9. doi: 10.1021/jm00088a009.

Abstract

The ester methyl [4-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy]phenoxy]acetate (8) has been identified as the most interesting member of a series of selective beta 3-adrenergic agonists of brown adipose tissue and thermogenesis in the rat. In vivo it acts mainly via the related acid 10. Potency was generally markedly reduced by placing substituents on the phenyl ring of the phenoxypropanolamine unit of 8; only the 2-fluoro analogue 16 had comparable potency to 8. Other structure-activity relationships are discussed. Further testing of 8 (ICI 198157) has shown that in the rat it stimulates the beta 3-adrenergic receptor in brown adipose tissue at doses lower than those at which it affects beta 1 and beta 2 adrenergic receptors in other tissues. It increases metabolic rate, as judged by an increase in oxygen consumption, and in the genetically obese Zucker rat it causes a reduced rate of weight gain. This class of compound may be useful in the treatment of obesity in man.

MeSH terms

  • Adipose Tissue, Brown / drug effects*
  • Adrenergic beta-Agonists / pharmacology*
  • Animals
  • Body Temperature Regulation / drug effects*
  • Oxygen / metabolism
  • Phenoxyacetates / chemistry
  • Phenoxyacetates / pharmacology*
  • Rats
  • Rats, Zucker
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Adrenergic beta-Agonists
  • Phenoxyacetates
  • ICI 198157
  • Oxygen