Direct syntheses of stereoisomers of 3-fluoro GABA and β-fluoroamine analogues of the calcium receptor (CaR) agonists, cinacalcet, tecalcet, fendilines and NPS R-467

Yohann J. G. Renault, Jiayin Diao, David B. Cordes, Katie Leach*, David O'Hagan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Synthetic routes following a sequential MacMillan organocatalytic asymmetric α-fluorination protocol for aldehydes and then reductive amination, have allowed ready access to bioactive β-fluoroamines. The approach is demonstrated with a short synthesis of (S)-3-fluoro-γ-aminobutyric acid (3F-GABA) and was extended to β-fluoroamine stereoisomers of cinacalcet, tecalcet, fendiline and NPS R-467, all allosteric modulators of the calcium receptor (CaR). Stereoisomers of the fluorinated calcimimetic analogues were then assayed in a CaR receptor assay and a comparison of β-fluoroamine matched pair stereoisomers revealed a binding mode preference to the receptor as deduced from conformations which will be favoured as a consequence of the electrostatic gauche effect.
Original languageEnglish
Pages (from-to)1532-1542
Number of pages11
JournalMedicinal Chemistry Research
Volume32
DOIs
Publication statusPublished - 24 Jul 2023

Keywords

  • Electrostatic gauche effect
  • Calimimetics
  • Cinacalcet
  • Fluorinated drugs
  • Calcium receptors
  • Asymmetric fluorination

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