RESUMO
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.
Assuntos
Conservadores da Densidade Óssea/síntese química , Colecalciferol/análogos & derivados , Osteoporose/tratamento farmacológico , Animais , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/química , Conservadores da Densidade Óssea/farmacologia , Calcitriol/análogos & derivados , Calcitriol/química , Calcitriol/farmacologia , Cálcio/sangue , Linhagem Celular , Colecalciferol/farmacologia , Colecalciferol/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Camundongos , Osteocalcina/análise , Osteocalcina/fisiologia , Osteoporose/fisiopatologia , Ratos , Ratos Sprague-Dawley , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/efeitos dos fármacos , Receptores de Calcitriol/genética , Esteroides/química , Relação Estrutura-AtividadeRESUMO
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).
Assuntos
Colecalciferol/química , Colecalciferol/uso terapêutico , Desenho de Fármacos , Psoríase/tratamento farmacológico , Animais , Colecalciferol/síntese química , Colecalciferol/farmacologia , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
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.
