title: Estrogen receptor ligands. Part 10: Chromanes: old scaffolds for new SERAMs.
abstract: The discovery, synthesis, and SAR of chromanes as ER alpha subtype selective ligands are described. X-ray studies revealed that the origin of the ER alpha-selectivity resulted from a C-4 trans methyl substitution to the cis-2,3-diphenyl-chromane platform. Selected compounds from this class demonstrated very potent in vivo antagonism of estradiol in an immature rat uterine weight assay, effectively inhibited ovariectomy-induced bone resorption in a 42 days treatment paradigm, and lowered serum cholesterol levels in ovx'd adult rat models. The best antagonists 8F and 12F also exhibited potent inhibition of MCF-7 cell growth and were shown to be estrogen receptor down-regulators (SERDs).
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, RY800-B107, Rahway, NJ 07065, USA. qiang_tan@merck.com
authors.forename: Qiang
authors.initials: Q
authors.lastname: Tan
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Blizzard
authors.forename: Jerry D
authors.initials: JD
authors.lastname: Morgan
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Birzin
authors.forename: Wanda
authors.initials: W
authors.lastname: Chan
authors.forename: Yi Tien
authors.initials: YT
authors.lastname: Yang
authors.forename: Lee-Yuh
authors.initials: LY
authors.lastname: Pai
authors.forename: Edward C
authors.initials: EC
authors.lastname: Hayes
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: DaSilva
authors.forename: Sudha
authors.initials: S
authors.lastname: Warrier
authors.forename: Joel
authors.initials: J
authors.lastname: Yudkovitz
authors.forename: Hilary A
authors.initials: HA
authors.lastname: Wilkinson
authors.forename: Nandini
authors.initials: N
authors.lastname: Sharma
authors.forename: Paula M D
authors.initials: PM
authors.lastname: Fitzgerald
authors.forename: Susan
authors.initials: S
authors.lastname: Li
authors.forename: Lawrence
authors.initials: L
authors.lastname: Colwell
authors.forename: John E
authors.initials: JE
authors.lastname: Fisher
authors.forename: Sharon
authors.initials: S
authors.lastname: Adamski
authors.forename: Alfred A
authors.initials: AA
authors.lastname: Reszka
authors.forename: Donald
authors.initials: D
authors.lastname: Kimmel
authors.forename: Frank
authors.initials: F
authors.lastname: DiNinno
authors.forename: Susan P
authors.initials: SP
authors.lastname: Rohrer
authors.forename: Leonard P
authors.initials: LP
authors.lastname: Freedman
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; D002460:Cell Line; D002839:Chromans / Q000737:chemistry* / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D015394:Molecular Structure; D009929:Organ Size; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D020845:Selective Estrogen Receptor Modulators / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014599:Uterus / Q000187:drug effects
chemical_list: D002839:Chromans; D047628:Estrogen Receptor alpha; D008024:Ligands; D020845:Selective Estrogen Receptor Modulators