Synthesis and structure-activity relationships of analogs of EM-652 (acolbifene), a pure selective estrogen receptor modulator. Study of nitrogen substitution.
EM-652 (acolbifene) analogs have been synthesized as selective estrogen receptor modulators. Substitution on the nitrogen atom of these 2H-1-benzopyran derivatives has been studied for its influence on antiestrogenic activity. Binding to the rat estrogen receptor, inhibition of estradiol-stimulated proliferation of T-47D breast cancer cells, as well as antiuterotrophic and uterotrophic activities in ovariectomized mice have been evaluated. 2H-1-Benzopyran 1b (EM-343, racemic form of EM-652), which contains a piperidine ring, shows the best pharmacological profile; RBA = 380, IC50 value = 0.110 nM (in T-47D cells), as well as 63% and 84% antiuterotrophic inhibitions at the 7.5 and 75 nmol doses, respectively.
Gauthier
Sylvain
S
Oncology and Molecular Endocrinology Research Center, Laval University Medical Center (CHUL), Québec G1V 4G2, Canada. sylvain.gauthier@crchul.ulaval.ca
Cloutier
Julie
J
Dory
Yves L
YL
Favre
Alexandre
A
Mailhot
Josée
J
Ouellet
Carl
C
Schwerdtfeger
Annette
A
Mérand
Yves
Y
Martel
Céline
C
Simard
Jacques
J
Labrie
Fernand
F
D000818:Animals; D001578:Benzopyrans / Q000737:chemistry; D002417:Cattle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020847:Estrogen Receptor Modulators / Q000378:metabolism* / Q000494:pharmacology*; D004967:Estrogens / Q000378:metabolism; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007328:Insulin / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008807:Mice, Inbred BALB C; D008956:Models, Chemical; D009584:Nitrogen / Q000737:chemistry*; D010880:Piperidines / Q000138:chemical synthesis*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism; D013329:Structure-Activity Relationship
D001578:Benzopyrans; D004791:Enzyme Inhibitors; D020847:Estrogen Receptor Modulators; D004967:Estrogens; D007328:Insulin; D010880:Piperidines; D011960:Receptors, Estrogen; C012121:ritetronium; D009584:Nitrogen