RESUMEN
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.
Asunto(s)
Conservadores de la Densidad Ósea/síntesis química , Colecalciferol/análogos & derivados , Osteoporosis/tratamiento farmacológico , Animales , Densidad Ósea/efectos de los fármacos , Conservadores de la Densidad Ósea/química , Conservadores de la Densidad Ósea/farmacología , Calcitriol/análogos & derivados , Calcitriol/química , Calcitriol/farmacología , Calcio/sangre , Línea Celular , Colecalciferol/farmacología , Colecalciferol/uso terapéutico , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Ratones , Osteocalcina/análisis , Osteocalcina/fisiología , Osteoporosis/fisiopatología , Ratas , Ratas Sprague-Dawley , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/efectos de los fármacos , Receptores de Calcitriol/genética , Esteroides/química , Relación Estructura-ActividadRESUMEN
Design, synthesis, and in vitro and in vivo evaluation of a series of antipsoriatic antedrugs having 16-en-22-oxa-vitamin D3 are described. Among the seven compounds examined, two are promising: ester 5c and amide 5f, both of which exhibit greater potent antiproliferation activity with lessened calcemic activity than the presently prescribed maxacalcitol (2).
Asunto(s)
Colecalciferol/química , Colecalciferol/uso terapéutico , Diseño de Fármacos , Psoriasis/tratamiento farmacológico , Animales , Colecalciferol/síntesis química , Colecalciferol/farmacología , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
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.
