title: 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 SF(5)-cinacalcet analogue 4 was prepared from meta-pentafluorosulfanyl benzyl alcohol and has ~75% agonist activity relative to cinacalcet 1 indicating that the SF(5) group can replace the CF(3) group and retain significant bioactivity.
authors.affiliation: University of St Andrews, School of Chemistry and Centre for Biomolecular Sciences, North Haugh, St Andrews, Fife, KY16 9ST, UK.
authors.forename: Poh Wai
authors.initials: PW
authors.lastname: Chia
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Brennan
authors.forename: Alexandra M Z
authors.initials: AM
authors.lastname: Slawin
authors.forename: Daniela
authors.initials: D
authors.lastname: Riccardi
authors.forename: David
authors.initials: D
authors.lastname: O'Hagan
mesh_terms: D000069449:Cinacalcet; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D005459:Fluorides / Q000737:chemistry*; D005461:Fluorine / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D044169:Receptors, Calcium-Sensing / Q000819:agonists*; D013329:Structure-Activity Relationship; D013457:Sulfur Compounds / Q000737:chemistry*
chemical_list: D009281:Naphthalenes; D044169:Receptors, Calcium-Sensing; D013457:Sulfur Compounds; C115613:sulfur pentafluoride cation; D005461:Fluorine; D005459:Fluorides; D000069449:Cinacalcet