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

doi:10.1007/s00044-023-03103-0

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 journal › Article › peer-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 language	English
Pages (from-to)	1532-1542
Number of pages	11
Journal	Medicinal Chemistry Research
Volume	32
DOIs	https://doi.org/10.1007/s00044-023-03103-0
Publication status	Published - 24 Jul 2023

Keywords

Electrostatic gauche effect
Calimimetics
Cinacalcet
Fluorinated drugs
Calcium receptors
Asymmetric fluorination

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title = "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",

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.",

keywords = "Electrostatic gauche effect, Calimimetics, Cinacalcet, Fluorinated drugs, Calcium receptors, Asymmetric fluorination",

author = "Renault, \{Yohann J. G.\} and Jiayin Diao and Cordes, \{David B.\} and Katie Leach and David O'Hagan",

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doi = "10.1007/s00044-023-03103-0",

language = "English",

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AU - Renault, Yohann J. G.

AU - Diao, Jiayin

AU - Cordes, David B.

AU - Leach, Katie

AU - O'Hagan, David

PY - 2023/7/24

Y1 - 2023/7/24

N2 - 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.

AB - 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.

KW - Electrostatic gauche effect

KW - Calimimetics

KW - Cinacalcet

KW - Fluorinated drugs

KW - Calcium receptors

KW - Asymmetric fluorination

UR - https://www.scopus.com/pages/publications/85165515055

U2 - 10.1007/s00044-023-03103-0

DO - 10.1007/s00044-023-03103-0

M3 - Article

SN - 1054-2523

VL - 32

SP - 1532

EP - 1542

JO - Medicinal Chemistry Research

JF - Medicinal Chemistry Research

ER -

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

Abstract

Keywords

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