Novel nonsecosteroidal vitamin D sub(3 carboxylic acid analogs for osteoporosis, and SAR analysis)

Novel vitamin D sub(3 analogs with carboxylic acid were explored, focusing on a nonsecosteroidal analog, LG190178, with a bisphenyl skeleton. From X-ray analysis of these analogs with vitamin D receptor (VDR), the carboxyl groups had very unique hydrogen bonding interactions in VDR and mimicked 1 alpha -hydroxy group and/or 3 beta -hydroxy group of 1 alpha ,25-dihydroxyvitamin D) sub(3). A highly potent analog, 6a, with good in vitro activity and pharmacokinetic profiles was identified from an SAR study. Compound 6a showed significant prevention of bone loss in a rat osteoporosis model by oral administration.