N2-Benzyl-N1-(1-(1-naphthyl)ethyl)-3-phenylpropane-1,2-diamines and conformationally restrained indole analogues: development of calindol as a new calcimimetic acting at the calcium sensing receptor

The synthesis and calcimimetic activities of two new families of compounds are described. The most active derivatives of the first family, N2-(2-chloro-(or 4-fluoro-)benzyl)-N1-(1-(1-naphthyl)ethyl)-3-phenylpropane-1,2-diamine (4b and 4d, respectively, tested at 10 μM) produced 98 ± 6% and 95 ± 4%, respectively, of the maximal stimulation of [3H]inositol phosphates production obtained by 10 mM Ca2+ in CHO cells expressing the rat calcium sensing receptor (CaSR). The second family of calcimimetics was obtained by conformationally restraining the compounds of type 4 to provide the 2-aminomethyl derivatives 5. One of these compounds, (R)-2-[N-(1-(1-naphthyl)ethyl)aminomethyl]indole ((R)-5a, calindol), displayed improved calcimimetic activity compared to 4b and 4d as well as stereoselectivity. In the presence of 2 mM Ca2+, calindol stimulated [3H]inositol phosphates accumulation with an EC50 of 1.0 ± 0.1 or 0.31 ± 0.05 μM in cells expressing the rat or the human CaSR, respectively. The calcimimetic activities of these novel compounds were shown to be due to a specific interaction with the CaSR.