Estrogen receptor ligands. II. Discovery of benzoxathiins as potent, selective estrogen receptor alpha modulators.
The discovery and synthesis of dihydrobenzoxathiins as potent, ERalpha subtype selective ligands are described. The most active analogue, 4-D, was found to be 50-fold selective in a competitive binding assay and 100-fold selective in a transactivation assay in HEK-293 cells. The alpha selectivity was postulated to lie in the interaction of the sulfur atom of the benzoxathiin ring with the two discriminating residues in the binding pocket of the receptor isoforms.
Kim
Seongkon
S
Department of Medicinal Chemistry, Atherosclerosis and Endocrinology, Merck Research Laboratories, P.O. Box 2000, 800-B109 Rahway, New Jersey 07065, USA. Seongkon_kim@merck.com
Wu
Jane Y
JY
Birzin
Elizabeth T
ET
Frisch
Katalin
K
Chan
Wanda
W
Pai
Lee-Yuh
LY
Yang
Yi Tien
YT
Mosley
Ralph T
RT
Fitzgerald
Paula M D
PM
Sharma
Nandini
N
Dahllund
Johanna
J
Thorsell
Ann-Gerd
AG
DiNinno
Frank
F
Rohrer
Susan P
SP
Schaeffer
James M
JM
Hammond
Milton L
ML
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002460:Cell Line; D018360:Crystallography, X-Ray; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005260:Female; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D009929:Organ Size / Q000187:drug effects; D010075:Oxathiins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation; D014599:Uterus / Q000187:drug effects
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D010075:Oxathiins; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators