Benzopyrans as selective estrogen receptor beta agonists (SERBAs). Part 4: functionalization of the benzopyran A-ring.
Benzopyrans are selective estrogen receptor (ER) beta agonists (SERBAs), which bind the ER receptor subtypes alpha and beta in opposite orientations. We have used structure based drug design to show that this unique phenomena can be exploited via substitution at the 8-position of the benzopyran A-ring to disrupt binding to ERalpha, thus improving ERbeta subtype selectivity. X-ray cocrystal structures with ERalpha and ERbeta are supportive of this approach to improve selectivity in this structural class.
Discovery Chemistry Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. norman@lilly.com
Bryan H
BH
Norman
Timothy I
TI
Richardson
Jeffrey A
JA
Dodge
Lance A
LA
Pfeifer
Gregory L
GL
Durst
Yong
Y
Wang
Jim D
JD
Durbin
Venkatesh
V
Krishnan
Sean R
SR
Dinn
Shengquan
S
Liu
John E
JE
Reilly
Kendal T
KT
Ryter
D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D047629:Estrogen Receptor beta / Q000819:agonists*; D008024:Ligands; D008958:Models, Molecular
D001578:Benzopyrans; D047629:Estrogen Receptor beta; D008024:Ligands