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  3. Development of novel β2-adrenergic receptor agonists for the stimulation of glucose uptake - The importance of chirality and ring size of cyclic amines

Development of novel β2-adrenergic receptor agonists for the stimulation of glucose uptake - The importance of chirality and ring size of cyclic amines

  • Bioorg Med Chem Lett. 2023 Nov 13:97:129562. doi: 10.1016/j.bmcl.2023.129562.
Krista Jaunsleine 1,  Linda Supe 1,  Jana Spura 1,  Sten van Beek 2,  Anna Sandström 2,  Jessica Olsen 2,  Carina Halleskog 2,  Tore Bengtsson 3,  Ilga Mutule 4,  Benjamin Pelcman 5
Affiliations

Affiliations

  • 1 Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia.
  • 2 Atrogi AB, Tomtebodavägen 6, SE-171 65 Solna, Sweden.
  • 3 Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-106 91 Stockholm, Sweden.
  • 4 Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia. Electronic address: ilga@osi.lv.
  • 5 Atrogi AB, Tomtebodavägen 6, SE-171 65 Solna, Sweden. Electronic address: benjamin@atrogi.com.
PMID: 37967654 DOI: 10.1016/j.bmcl.2023.129562
Abstract

β2-Adrenergic receptor (β2AR) agonists have been reported to stimulate glucose uptake (GU) by skeletal muscle cells and are therefore highly interesting as a possible treatment for type 2 diabetes (T2D). The chirality of compounds often has a great impact on the activity of β2AR agonists, although this has thus far not been investigated for GU. Here we report the GU for a selection of synthesized acyclic and cyclic β-hydroxy-3-fluorophenethylamines. For the N-butyl and the N-(2-pentyl) compounds, the (R) and (R,R) (3d and 7e) stereoisomers induced the highest GU. When the compounds contained a saturated nitrogen containing 4- to 7-membered heterocycle, the (R,R,R) enantiomer of the azetidine (8a) and the pyrrolidine (9a) had the highest activity. Altogether, these results provide pivotal information for designing novel β2AR agonist for the treatment of T2D.

Keywords

Cyclic amines; Diastereoselective synthesis; Muscle glucose uptake; β-Adrenergic receptor agonist; β-Hydroxy-phenethylamines.

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