Design, synthesis and biological evaluation of bis(hydroxyphenyl) azoles as potent and selective non-steroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) for the treatment of estrogen-dependent diseases.
The 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) catalyses the reduction of the weakly active estrone (E1) into the most potent estrogen, 17beta-estradiol (E2). E2 stimulates the growth of hormone-dependent diseases via activation of the estrogen receptors (ERs). 17beta-HSD1 is often over-expressed in breast cancer cells. Thus, it is an attractive target for the treatment of mammary tumours. The combination of a ligand- and a structure-based drug design approach led to the identification of bis(hydroxyphenyl) azoles as potential inhibitors of 17beta-HSD1. Different azoles and hydroxy substitution patterns were investigated. The compounds were evaluated for activity and selectivity with regard to 17beta-HSD2, ERalpha and ERbeta. The most potent compound is 3-[5-(4-hydroxyphenyl)-1,3-oxazol-2-yl]phenol (18, IC(50)=0.31 microM), showing very good selectivity, high cell permeability and medium CaCo-2 permeability.
8.2 Pharmaceutical and Medicinal Chemistry, Saarland University, PO Box 15 11 50, D-66041 Saarbrücken, Germany.
Emmanuel
E
Bey
Sandrine
S
Marchais-Oberwinkler
Patricia
P
Kruchten
Martin
M
Frotscher
Ruth
R
Werth
Alexander
A
Oster
Oztekin
O
Algül
Alexander
A
Neugebauer
Rolf W
RW
Hartmann
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018931:Antineoplastic Agents, Hormonal / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001393:Azoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D018938:Caco-2 Cells; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004967:Estrogens / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010539:Permeability; D013329:Structure-Activity Relationship
D018931:Antineoplastic Agents, Hormonal; D001393:Azoles; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D004967:Estrogens; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase