Design and synthesis of calindol derivatives as potent and selective calcium sensing receptor agonists. - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Bioorganic and Medicinal Chemistry Année : 2016

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

Résumé

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.
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Dates et versions

hal-01366761 , version 1 (15-09-2016)

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Lionel Kiefer, Floriane Beaumard, Tatiana Gorojankina, Hélène Faure, Martial Ruat, et al.. Design and synthesis of calindol derivatives as potent and selective calcium sensing receptor agonists.. Bioorganic and Medicinal Chemistry, 2016, 24 (4), pp.554-69. ⟨10.1016/j.bmc.2015.12.019⟩. ⟨hal-01366761⟩
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