Allosteric agonists of the calcium receptor (CaR): fluorine and SF5 analogues of cinacalcet

Three selectively fluorinated cinacalcet analogues are prepared and their activity as calcium-sensing receptor (CaR) agonists is assessed. Individual (2R, 1'R)-2 and (2S, 1'R)-3 fluorocinacalcet diastereoisomers were prepared using the MacMillan asymmetric fluorination reaction. Assays with the recombinant human CaR revealed that both diastereoisomers have a similar potency to each other although slightly lower (75-80%) than that of cinacalcet 1. The SF5-cinacalcet analogue 4 was prepared from meta-pentafluorosulfanyl benzyl alcohol and has similar to 75% agonist activity relative to cinacalcet 1 indicating that the SF5 group can replace the CF3 group and retain significant bioactivity.