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.
Résumé
The synthesis and calcimimetic activities of two new families of compounds are described. The most active derivatives of the first family, N(2)-(2-chloro-(or 4-fluoro-)benzyl)-N(1)-(1-(1-naphthyl)ethyl)-3-phenylpropane-1,2-diamine (4b and 4d, respectively, tested at 10 microM) produced 98+/-6% and 95+/-4%, respectively, of the maximal stimulation of [(3)H]inositol phosphates production obtained by 10mM Ca(2+) 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 2mM Ca(2+), calindol stimulated [(3)H]inositol phosphates accumulation with an EC(50) of 1.0+/-0.1 or 0.31+/-0.05 microM 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.