Estrogen receptor ligands. Part 10: Chromanes: old scaffolds for new SERAMs.
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).
Tan
Qiang
Q
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, RY800-B107, Rahway, NJ 07065, USA. qiang_tan@merck.com
Blizzard
Timothy A
TA
Morgan
Jerry D
JD
Birzin
Elizabeth T
ET
Chan
Wanda
W
Yang
Yi Tien
YT
Pai
Lee-Yuh
LY
Hayes
Edward C
EC
DaSilva
Carolyn A
CA
Warrier
Sudha
S
Yudkovitz
Joel
J
Wilkinson
Hilary A
HA
Sharma
Nandini
N
Fitzgerald
Paula M D
PM
Li
Susan
S
Colwell
Lawrence
L
Fisher
John E
JE
Adamski
Sharon
S
Reszka
Alfred A
AA
Kimmel
Donald
D
DiNinno
Frank
F
Rohrer
Susan P
SP
Freedman
Leonard P
LP
Schaeffer
James M
JM
Hammond
Milton L
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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
D002839:Chromans; D047628:Estrogen Receptor alpha; D008024:Ligands; D020845:Selective Estrogen Receptor Modulators