title: Estrogen receptor ligands. II. Discovery of benzoxathiins as potent, selective estrogen receptor alpha modulators.
abstract: 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.
authors.affiliation: 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
authors.forename: Seongkon
authors.initials: S
authors.lastname: Kim
authors.forename: Jane Y
authors.initials: JY
authors.lastname: Wu
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Birzin
authors.forename: Katalin
authors.initials: K
authors.lastname: Frisch
authors.forename: Wanda
authors.initials: W
authors.lastname: Chan
authors.forename: Lee-Yuh
authors.initials: LY
authors.lastname: Pai
authors.forename: Yi Tien
authors.initials: YT
authors.lastname: Yang
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Mosley
authors.forename: Paula M D
authors.initials: PM
authors.lastname: Fitzgerald
authors.forename: Nandini
authors.initials: N
authors.lastname: Sharma
authors.forename: Johanna
authors.initials: J
authors.lastname: Dahllund
authors.forename: Ann-Gerd
authors.initials: AG
authors.lastname: Thorsell
authors.forename: Frank
authors.initials: F
authors.lastname: DiNinno
authors.forename: Susan P
authors.initials: SP
authors.lastname: Rohrer
authors.forename: James M
authors.initials: JM
authors.lastname: Schaeffer
authors.forename: Milton L
authors.initials: ML
authors.lastname: Hammond
mesh_terms: 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
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D010075:Oxathiins; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators