2. Academic Validation
  3. Design and synthesis of calindol derivatives as potent and selective calcium sensing receptor agonists

Design and synthesis of calindol derivatives as potent and selective calcium sensing receptor agonists

  • Bioorg Med Chem. 2016 Feb 15;24(4):554-69. doi: 10.1016/j.bmc.2015.12.019.
Lionel Kiefer 1,  Floriane Beaumard 1,  Tatiana Gorojankina 2,  Hélène Faure 2,  Martial Ruat 2,  Robert H Dodd 3
Affiliations

Affiliations

  • 1 Institut de Chimie des Substances Naturelles, UPR-2301, CNRS, 1 Avenue de la Terrasse, F-91198 Gif-sur-Yvette, France.
  • 2 CNRS, UMR-9197, Neuroscience Paris-Saclay, Signal Transduction and Developmental Neuropharmacology Team, 1 Avenue de la Terrasse, F-91198 Gif-sur-Yvette, France.
  • 3 Institut de Chimie des Substances Naturelles, UPR-2301, CNRS, 1 Avenue de la Terrasse, F-91198 Gif-sur-Yvette, France. Electronic address: robert.dodd@cnrs.fr.
PMID: 26752095 DOI: 10.1016/j.bmc.2015.12.019
Abstract

We report the first comprehensive structure-activity study of calindol (4, (R)-N-[(1H-indol-2-yl)methyl]-1-(1-naphthyl)ethanamine), a positive allosteric modulator, or calcimimetic, of the calcium sensing receptor (CaSR). While replacement of the naphthyl moiety of calindol by other aromatic groups (phenyl, biphenyl) was largely detrimental to calcimimetic activity, incorporation of substituents on the 4, 5 or 7 position of the indole portion of calindol was found to provide either equipotent derivatives compared to calindol (e.g., 4-phenyl, 4-hydroxy, 5-hydroxycalindol 44, 52, 53) or, in the case of 7-nitrocalindol (51), a 6-fold more active calcimimetic displaying an EC50 of 20nM. Unlike calindol, the more active CaSR calcimimetics were shown not to act as antagonists of the closely related GPRC6A receptor, suggesting a more selective profile for these new analogues.

Keywords

Calcimimetic; Calcium sensing receptor; Calindol; Hyperparathyroidism; Indole; Parathyroid hormone.

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