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

Abstract

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 ∼75% agonist activity relative to cinacalcet 1 indicating that the SF₅ group can replace the CF₃ group and retain significant bioactivity.