ABSTRACT
Novel vitamin D(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 1α-hydroxy group and/or 3ß-hydroxy group of 1α,25-dihydroxyvitamin D(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.
Subject(s)
Bone Density Conservation Agents/chemical synthesis , Cholecalciferol/analogs & derivatives , Osteoporosis/drug therapy , Animals , Bone Density/drug effects , Bone Density Conservation Agents/chemistry , Bone Density Conservation Agents/pharmacology , Calcitriol/analogs & derivatives , Calcitriol/chemistry , Calcitriol/pharmacology , Calcium/blood , Cell Line , Cholecalciferol/pharmacology , Cholecalciferol/therapeutic use , Drug Evaluation, Preclinical , Female , Humans , Mice , Osteocalcin/analysis , Osteocalcin/physiology , Osteoporosis/physiopathology , Rats , Rats, Sprague-Dawley , Receptors, Calcitriol/agonists , Receptors, Calcitriol/drug effects , Receptors, Calcitriol/genetics , Steroids/chemistry , Structure-Activity RelationshipSubject(s)
Acetanilides/chemistry , Benzophenones/chemistry , Boron Compounds/chemistry , Boron/chemistry , Carbon/chemistry , Proteasome Endopeptidase Complex/metabolism , Acetanilides/chemical synthesis , Acetanilides/toxicity , Acetates/chemical synthesis , Acetates/chemistry , Acetates/toxicity , Benzophenones/chemical synthesis , Benzophenones/toxicity , Boron Compounds/chemical synthesis , Boron Compounds/toxicity , Drug Evaluation, Preclinical , HeLa Cells , HumansABSTRACT
A series of 16-en-22-oxa-derivatives of vitamin D3 based on the structure of maxacalcitol (2) were prepared. Maxacalcitol is currently used topically for the treatment of psoriasis and is recognized as the most successful antedrug of natural vitamin D(3) because it retains the original antiproliferative activity of calcitriol without increased calcemic activity. We introduced 16-olefinic functionality to accelerate the oxidative metabolism of the drug in liver, presumed to be essential for the reduction of calcemic activity, and modified the side-chain moiety by placing the 22-oxygen on the more labile allylic carbon center. Novel 22-oxa analogs (7a-i), carrying either the 24-alkynyl bond or 24-hydroxy functionality in addition to the 16-double bond were synthesized and their pharmacokinetics were evaluated.