New insights into the SAR and binding modes of bis(hydroxyphenyl)thiophenes and -benzenes: influence of additional substituents on 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) inhibitory activity and selectivity.
17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1) is responsible for the catalytic reduction of weakly active E1 to highly potent E2. E2 stimulates the proliferation of hormone-dependent diseases via activation of the estrogen receptor alpha (ERalpha). Because of the overexpression of 17beta-HSD1 in mammary tumors, this enzyme should be an attractive target for the treatment of estrogen-dependent pathologies. Recently, we have reported on a series of potent 17beta-HSD1 inhibitors: bis(hydroxyphenyl) azoles, thiophenes, and benzenes. In this paper, different substituents are introduced into the core structure and the biological properties of the corresponding inhibitors are evaluated. Computational methods and analysis of different X-rays of 17beta-HSD1 lead to identification of two different binding modes for these inhibitors. The fluorine compound 23 exhibits an IC(50) of 8 nM and is the most potent nonsteroidal inhibitor described so far. It also shows a high selectivity (17beta-HSD2, ERalpha) and excellent pharmacokinetic properties after peroral application to rats.
Bey
Emmanuel
E
Pharmaceutical and Medicinal Chemistry, Saarland University, P.O. Box 15 11 50, D-66041 Saarbrucken, Germany.
Marchais-Oberwinkler
Sandrine
S
Negri
Matthias
M
Kruchten
Patricia
P
Oster
Alexander
A
Klein
Tobias
T
Spadaro
Alessandro
A
Werth
Ruth
R
Frotscher
Martin
M
Birk
Barbara
B
Hartmann
Rolf W
RW
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000284:Administration, Oral; D000818:Animals; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D065607:Cytochrome P-450 Enzyme Inhibitors; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors; D047628:Estrogen Receptor alpha / Q000737:chemistry; D047629:Estrogen Receptor beta / Q000737:chemistry; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008099:Liver / Q000201:enzymology; D008297:Male; D008958:Models, Molecular; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013730:Terphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C545542:2-fluoro-4-(5-(3-hydroxyphenyl)-2-thienyl)phenol; D001555:Benzene Derivatives; D001713:Biphenyl Compounds; D065607:Cytochrome P-450 Enzyme Inhibitors; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D007527:Isoenzymes; D010636:Phenols; D013730:Terphenyl Compounds; D013844:Thiazoles; D013876:Thiophenes; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; D004960:Estradiol Dehydrogenases; C523763:HSD17B2 protein, human