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 language | English |
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Pages (from-to) | 1532-1542 |
Number of pages | 11 |
Journal | Medicinal Chemistry Research |
Volume | 32 |
DOIs | |
Publication status | Published - 24 Jul 2023 |
Keywords
- Electrostatic gauche effect
- Calimimetics
- Cinacalcet
- Fluorinated drugs
- Calcium receptors
- Asymmetric fluorination